rs63751220

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001001557.4(GDF6):c.866T>C(p.Leu289Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000137 in 1,502,488 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 1 hom. )

Consequence

GDF6
NM_001001557.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.59

Publications

7 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039397776).

BP6

Variant 8-96145065-A-G is Benign according to our data. Variant chr8-96145065-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8372.

BS2

High AC in GnomAd4 at 123 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF6	NM_001001557.4 link	c.866T>C	p.Leu289Pro	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.866T>C	p.Leu289Pro	missense_variant	Exon 2 of 2	1	NM_001001557.4	ENSP00000287020.4		Q6KF10

Frequencies

GnomAD3 genomes

AF:

0.000811

AC:

123

AN:

151754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD2 exomes

AF:

0.0000636

AC:

AN:

141432

AF XY:

0.0000494

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000615

AC:

AN:

1350626

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

668560

show subpopulations

African (AFR)

AF:

0.00255

AC:

AN:

28284

American (AMR)

AF:

0.0000300

AC:

AN:

33310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23570

East Asian (EAS)

AF:

0.00

AC:

AN:

32112

South Asian (SAS)

AF:

0.00

AC:

AN:

72542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33800

Middle Eastern (MID)

AF:

0.000209

AC:

AN:

4782

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1066380

Other (OTH)

AF:

0.000125

AC:

AN:

55846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000810

AC:

123

AN:

151862

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.00294

AC:

122

AN:

41472

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67856

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000820

ESP6500AA

AF:

0.00132

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000125

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Klippel-Feil syndrome 1, autosomal dominant

Pathogenic:1

Aug 01, 2008

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

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:1

Jun 06, 2016

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The L289P variant in the GDF6 gene has been reported previously in two unrelated patients with Klippel-Feil syndrome: an adult male with short neck, mirror movements, and left Sprengel anomaly, and a fetus with multiple segmentation abnormalities affecting the entire spine and ribs (Tassabehji et al., 2008). Both cases were said to be sporadic, but there is no evidence that family studies were performed. The L289P variant was not observed at any significant frequency in approximately 4500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L289P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variants in a nearby residue, E292D, has been reported in the Human Gene Mutation Database in association with Leber congenital amaurosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret L289P as a variant of uncertain significance. -

GDF6-related disorder

Benign:1

Feb 08, 2024

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 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Pathogenic

0.78

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.70

T;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.039

T;T

MetaSVM

Uncertain

0.058

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

5.6

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.2

D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.052

T;D

Polyphen

1.0

D;.

Vest4

0.40

MVP

0.94

MPC

2.4

ClinPred

0.41

GERP RS

3.4

Varity_R

0.82

gMVP

0.78

Mutation Taster

=16/84

disease causing

(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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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