8-96144995-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001001557.4(GDF6):c.936G>C(p.Ser312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,379,714 control chromosomes in the GnomAD database, including 1,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (82 hom., cov: 32)
  • Exomes 𝑓: 0.038 (965 hom.)
• Consequence: GDF6 NM_001001557.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.18

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-96144995-C-G is Benign according to our data. Variant chr8-96144995-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 256851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-96144995-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0262 (3960/151126) while in subpopulation NFE AF= 0.0398 (2693/67712). AF 95% confidence interval is 0.0385. There are 82 homozygotes in gnomad4. There are 1893 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 82 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF6	NM_001001557.4	c.936G>C	p.Ser312=	synonymous_variant	2/2	ENST00000287020.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF6	ENST00000287020.7	c.936G>C	p.Ser312=	synonymous_variant	2/2	1	NM_001001557.4	P1

Frequencies

GnomAD3 genomes AF: 0.0262 AC: 3960 AN: 151018 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.00714

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0398

Gnomad OTH AF: 0.0303

GnomAD3 exomes AF: 0.0334 AC: 1837 AN: 54992 Hom.: 46 AF XY: 0.0297 AC XY: 945 AN XY: 31814

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.0329

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00900

Gnomad FIN exome AF: 0.0237

Gnomad NFE exome AF: 0.0542

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0375 AC: 46106 AN: 1228588 Hom.: 965 Cov.: 31 AF XY: 0.0367 AC XY: 22059 AN XY: 600532

Gnomad4 AFR exome AF: 0.00599

Gnomad4 AMR exome AF: 0.0278

Gnomad4 ASJ exome AF: 0.0314

Gnomad4 EAS exome AF: 0.0000372

Gnomad4 SAS exome AF: 0.00943

Gnomad4 FIN exome AF: 0.0207

Gnomad4 NFE exome AF: 0.0418

Gnomad4 OTH exome AF: 0.0342

GnomAD4 genome AF: 0.0262 AC: 3960 AN: 151126 Hom.: 82 Cov.: 32 AF XY: 0.0256 AC XY: 1893 AN XY: 73898

Gnomad4 AFR AF: 0.00712

Gnomad4 AMR AF: 0.0273

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0398

Gnomad4 OTH AF: 0.0300

Alfa AF: 0.0301 Hom.: 11

Bravo AF: 0.0266

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Klippel-Feil syndrome 1, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.5
Dann	Benign	0.56

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: rs148861809; hg19: chr8-97157223; COSMIC: COSV99747553; COSMIC: COSV99747553;