rs121909352

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001001557.4(GDF6):c.746C>A(p.Ala249Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,496,680 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 15 hom. )

Consequence

GDF6
NM_001001557.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:6B:5

Conservation

PhyloP100: 0.269

Publications

16 publications found

Variant links:

Genes affected

GDF6 (HGNC:4221): (growth differentiation factor 6) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein is required for normal formation of some bones and joints in the limbs, skull, and axial skeleton. Mutations in this gene are associated with Klippel-Feil syndrome, microphthalmia, and Leber congenital amaurosis. [provided by RefSeq, Sep 2016]

GDF6 Gene-Disease associations (from GenCC):

Klippel-Feil syndrome 1, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
microphthalmia
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
multiple synostoses syndrome 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
isolated Klippel-Feil syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated microphthalmia 4
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis 17
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GDF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036596745).

BS2

High AC in GnomAd4 at 298 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF6	NM_001001557.4 link	c.746C>A	p.Ala249Glu	missense_variant	Exon 2 of 2	ENST00000287020.7	NP_001001557.1	Q6KF10A0A0S2A5D6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7 link	c.746C>A	p.Ala249Glu	missense_variant	Exon 2 of 2	1	NM_001001557.4	ENSP00000287020.4		Q6KF10

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

299

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00353

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00198

AC:

192

AN:

97088

AF XY:

0.00216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000384

Gnomad NFE exome

AF:

0.00401

Gnomad OTH exome

AF:

0.00172

GnomAD4 exome

AF:

0.00386

AC:

5191

AN:

1344460

Hom.:

Cov.:

AF XY:

0.00376

AC XY:

2492

AN XY:

662802

show subpopulations

African (AFR)

AF:

0.000767

AC:

AN:

27390

American (AMR)

AF:

0.00191

AC:

AN:

31372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23658

East Asian (EAS)

AF:

0.00

AC:

AN:

31694

South Asian (SAS)

AF:

0.0000267

AC:

AN:

74828

European-Finnish (FIN)

AF:

0.000245

AC:

AN:

32702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4202

European-Non Finnish (NFE)

AF:

0.00464

AC:

4926

AN:

1062610

Other (OTH)

AF:

0.00311

AC:

174

AN:

56004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

316

632

947

1263

1579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00196

AC:

298

AN:

152220

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41566

American (AMR)

AF:

0.00176

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00353

AC:

240

AN:

67980

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00226

Hom.:

Bravo

AF:

0.00215

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ExAC

AF:

0.000992

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

May 18, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Does not segregate with Chiari Malformation type 1 in all affected individuals in published literature (PMID: 23620759); Published functional studies suggest this variant results in a decrease of activity as compared to wild-type (PMID: 23307924); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20494911, 32483926, 29343940, 19129173, 21864080, 23307924, 31068177, 29260090, 30755392, 32737436, 38025229, 18425797, 25457163, 23620759) -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GDF6: BS2 -

Klippel-Feil syndrome 1, autosomal dominant

Pathogenic:1Uncertain:1

Aug 13, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: low reads, pathogenic by OMIM in ClinVar, implicated in different pathologies -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Isolated microphthalmia 4

Pathogenic:1

Apr 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Congenital anomaly of kidney and urinary tract

Pathogenic:1

Feb 15, 2024

Weber Lab, Hannover Medical School

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Klippel-Feil syndrome 1, autosomal dominant;C1968949:Congenital anomaly of kidney and urinary tract

Pathogenic:1

Feb 15, 2024

Weber Lab, Hannover Medical School

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Leber congenital amaurosis 17

Pathogenic:1

Apr 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Klippel-Feil syndrome 1, autosomal dominant;C2751307:Isolated microphthalmia 4;C3150968:Microphthalmia, isolated, with coloboma 6;C3715164:Leber congenital amaurosis 17;C4693531:Multiple synostoses syndrome 4

Uncertain:1

May 02, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GDF6-related disorder

Benign:1

Nov 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Klippel-Feil syndrome 1, autosomal dominant;C2751307:Isolated microphthalmia 4;C3150968:Microphthalmia, isolated, with coloboma 6;C3715164:Leber congenital amaurosis 17

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Klippel-Feil syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

5.9

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.38

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.36

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.92

L;.

PhyloP100

0.27

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.92

N;.

REVEL

Benign

0.27

Sift

Benign

0.093

T;.

Sift4G

Benign

0.59

T;D

Polyphen

0.012

B;.

Vest4

0.10

MVP

0.97

MPC

0.94

ClinPred

0.013

GERP RS

0.81

Varity_R

0.065

gMVP

0.28

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs121909352

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over