rs121909353

Positions:

chr8-96144660-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001001557.4(GDF6):c.1271A>G(p.Lys424Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000694 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

GDF6
NM_001001557.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1B:2

Conservation

PhyloP100: 4.22

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017830074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF6	NM_001001557.4 linkuse as main transcript	c.1271A>G	p.Lys424Arg	missense_variant	2/2	ENST00000287020.7	NP_001001557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7 linkuse as main transcript	c.1271A>G	p.Lys424Arg	missense_variant	2/2	1	NM_001001557.4	ENSP00000287020	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000211

AC:

AN:

250766

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00277

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00244

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Klippel-Feil syndrome 1, autosomal dominant

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2009	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Dec 30, 2014	Our laboratory reported dual molecular diagnoses in GDF6 (NM_001001557.2, c.1271A>G) and SOX10 (NM_006941.3, c.316C>G) in one individual with reported features of developmental delay and unilateral hearing loss. The GDF6 variant has been previously reported as disease-causing (PMID 19129173). Additionally, this same variant was also seen in a 48-year-old male with migraines, white matter changes, intracerebral hemorrhages, episodes of hemiparesis and dysarthria, renal cysts, hematuria. -

Autosomal dominant Parkinson disease 8;C1861689:Klippel-Feil syndrome 1, autosomal dominant

Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Codex Genetics Limited

Feb 28, 2019

- -

Leber congenital amaurosis 17

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

- -

Klippel-Feil syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.59

Eigen

Benign

0.00083

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0060

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.17

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.96

REVEL

Uncertain

0.57

Sift

Benign

0.86

Sift4G

Benign

0.85

Polyphen

0.66

Vest4

0.22

MVP

0.95

MPC

1.1

ClinPred

0.063

GERP RS

2.6

Varity_R

0.16

gMVP

0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over