rs62516290

chr8-96160259-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001001557.4(GDF6):c.406+28C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0785 in 1,612,804 control chromosomes in the GnomAD database, including 5,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (397 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5314 hom.)
• Consequence: GDF6 NM_001001557.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.20

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-96160259-G-T is Benign according to our data. Variant chr8-96160259-G-T is described in ClinVar as [Benign]. Clinvar id is 256848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-96160259-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF6	NM_001001557.4	c.406+28C>A		intron_variant		ENST00000287020.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF6	ENST00000287020.7	c.406+28C>A		intron_variant		1	NM_001001557.4	P1

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9634 AN: 152200 Hom.: 396 Cov.: 33

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.0936

Gnomad OTH AF: 0.0737

GnomAD3 exomes AF: 0.0624 AC: 15589 AN: 249932 Hom.: 660 AF XY: 0.0629 AC XY: 8511 AN XY: 135334

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.0564

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0163

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.0923

Gnomad OTH exome AF: 0.0845

GnomAD4 exome AF: 0.0801 AC: 116965 AN: 1460486 Hom.: 5314 Cov.: 32 AF XY: 0.0787 AC XY: 57183 AN XY: 726708

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.0586

Gnomad4 ASJ exome AF: 0.0627

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0160

Gnomad4 FIN exome AF: 0.0553

Gnomad4 NFE exome AF: 0.0926

Gnomad4 OTH exome AF: 0.0727

GnomAD4 genome AF: 0.0632 AC: 9633 AN: 152318 Hom.: 397 Cov.: 33 AF XY: 0.0601 AC XY: 4477 AN XY: 74480

Gnomad4 AFR AF: 0.0273

Gnomad4 AMR AF: 0.0695

Gnomad4 ASJ AF: 0.0605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0487

Gnomad4 NFE AF: 0.0937

Gnomad4 OTH AF: 0.0729

Alfa AF: 0.0794 Hom.: 91

Bravo AF: 0.0647

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	8.9
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62516290; hg19: chr8-97172487;