8-96145336-C-T

Position:

chr8-96145336-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001001557.4(GDF6):c.595G>A(p.Ala199Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000214 in 1,540,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GDF6
NM_001001557.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 1.33

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.099833876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF6	NM_001001557.4 linkuse as main transcript	c.595G>A	p.Ala199Thr	missense_variant	2/2	ENST00000287020.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF6	ENST00000287020.7 linkuse as main transcript	c.595G>A	p.Ala199Thr	missense_variant	2/2	1	NM_001001557.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000495

AC:

AN:

141442

Hom.:

AF XY:

0.0000646

AC XY:

AN XY:

77414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000216

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000351

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000223

AC:

AN:

1388318

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

685366

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000225

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000458

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Microphthalmia, isolated, with coloboma 6

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

Leber congenital amaurosis 17

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 199 of the GDF6 protein (p.Ala199Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with microphthalmia (PMID: 19864492, 23307924). ClinVar contains an entry for this variant (Variation ID: 30159). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GDF6 protein function. Experimental studies have shown that this missense change affects GDF6 function (PMID: 19864492, 23307924). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.34

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.62

T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.52

N;.;.

MutationTaster

Benign

0.73

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.99

N;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.35

T;.;.

Sift4G

Benign

0.23

T;T;T

Polyphen

0.015

B;.;.

Vest4

0.045

MutPred

0.80

Gain of glycosylation at A199 (P = 0.0303);Gain of glycosylation at A199 (P = 0.0303);Gain of glycosylation at A199 (P = 0.0303);

MVP

0.97

MPC

0.82

ClinPred

0.041

GERP RS

-0.86

Varity_R

0.086

gMVP

0.30

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