rs121909354

chr8-96160568-C-Achr8-96160568-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001001557.4(GDF6):c.125G>T(p.Gly42Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,674 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G42A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00099 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000096 (1 hom.)
• Consequence: GDF6 NM_001001557.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006322086).
• BP6: Variant 8-96160568-C-A is Benign according to our data. Variant chr8-96160568-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 8374.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF6	NM_001001557.4	c.125G>T	p.Gly42Val	missense_variant	1/2	ENST00000287020.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF6	ENST00000287020.7	c.125G>T	p.Gly42Val	missense_variant	1/2	1	NM_001001557.4	P1

Frequencies

GnomAD3 genomes AF: 0.000926 AC: 141 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000233 AC: 58 AN: 248438 Hom.: 0 AF XY: 0.000178 AC XY: 24 AN XY: 134900

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461346 Hom.: 1 Cov.: 32 AF XY: 0.0000812 AC XY: 59 AN XY: 727014

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.000967 AC XY: 72 AN XY: 74482

Gnomad4 AFR AF: 0.00344

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.00100

ESP6500AA AF: 0.00500 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000280 AC: 34

Asia WGS AF: 0.00116 AC: 4 AN: 3474

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Klippel-Feil syndrome 1, autosomal dominant 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.34	N;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	D;.;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.87	P;.;.
Vest4		0.38
MVP		0.64
MPC		1.1
ClinPred		0.038	T
GERP RS		0.89
Varity_R		0.21
gMVP		0.42

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

Other links and lift over

dbSNP: rs121909354; hg19: chr8-97172796;