Variant rs121909356 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4BP6_Moderate

The NM_001001557.4(GDF6):c.980C>A(p.Pro327His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,549,600 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Benign (★).

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

GDF6
NM_001001557.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter P:1B:1

Conservation

PhyloP100: 0.307

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27928758).

BP6

Variant 8-96144951-G-T is Benign according to our data. Variant chr8-96144951-G-T is described in ClinVar as [Benign]. Clinvar id is 8376.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF6	NM_001001557.4 linkuse as main transcript	c.980C>A	p.Pro327His	missense_variant	2/2	ENST00000287020.7	NP_001001557.1	Q6KF10A0A0S2A5D6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7 linkuse as main transcript	c.980C>A	p.Pro327His	missense_variant	2/2	1	NM_001001557.4	ENSP00000287020.4		Q6KF10

Frequencies

GnomAD3 genomes

AF:

0.0000926

AC:

AN:

151142

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:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000515

AC:

AN:

149532

Hom.:

AF XY:

0.000754

AC XY:

AN XY:

80858

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:

0.00333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000177

AC:

247

AN:

1398350

Hom.:

Cov.:

AF XY:

0.000272

AC XY:

188

AN XY:

690846

show subpopulations

Gnomad4 AFR exome

AF:

0.0000632

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00293

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.25e-7

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.0000926

AC:

AN:

151250

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

73904

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:

0.00290

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000437

AC:

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Isolated microphthalmia 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 2009

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.32

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.30

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.35

REVEL

Uncertain

0.48

Sift

Benign

0.54

Sift4G

Benign

0.54

Polyphen

0.0

Vest4

0.68

MutPred

0.18

Loss of glycosylation at P327 (P = 0.0254);

MVP

0.88

MPC

0.93

ClinPred

0.013

GERP RS

3.7

Varity_R

0.18

gMVP

0.58

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