rs77859767

chr8-96145563-G-Achr8-96145563-G-Cchr8-96145563-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.407-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,596,908 control chromosomes in the GnomAD database, including 1,674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (877 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (797 hom.)
• Consequence: GDF6 NM_001001557.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.63

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=-0.52).
• BP6: Variant 8-96145563-G-A is Benign according to our data. Variant chr8-96145563-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF6	NM_001001557.4	c.407-39C>T		intron_variant		ENST00000287020.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF6	ENST00000287020.7	c.407-39C>T		intron_variant		1	NM_001001557.4	P1

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8837 AN: 152194 Hom.: 873 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0152 AC: 3468 AN: 228560 Hom.: 282 AF XY: 0.0120 AC XY: 1526 AN XY: 126840

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000499

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.000885

Gnomad OTH exome AF: 0.00895

GnomAD4 exome AF: 0.00697 AC: 10072 AN: 1444596 Hom.: 797 Cov.: 31 AF XY: 0.00629 AC XY: 4520 AN XY: 718998

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000490

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.000764

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0582 AC: 8867 AN: 152312 Hom.: 877 Cov.: 32 AF XY: 0.0556 AC XY: 4139 AN XY: 74480

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0187

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000564

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.00638 Hom.: 6

Bravo AF: 0.0664

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

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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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	15
Dann	Benign	0.94

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: rs77859767; hg19: chr8-97157791;