dbSNP rs77859767: GDF6:c.407-39C>T (chr8-96145563-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.63

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 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 rank	MANE	Protein	UniProt
GDF6	NM_001001557.4 link	c.407-39C>T		intron_variant	Intron 1 of 1	ENST00000287020.7	NP_001001557.1	Q6KF10A0A0S2A5D6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7 link	c.407-39C>T		intron_variant	Intron 1 of 1	1	NM_001001557.4	ENSP00000287020.4		Q6KF10

Frequencies

GnomAD3 genomes

AF:

0.0581

AC:

8837

AN:

152194

Hom.:

873

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00629

AC XY:

4520

AN XY:

718998

show subpopulations

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.:

AF XY:

0.0556

AC XY:

4139

AN XY:

74480

show subpopulations

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.:

Bravo

AF:

0.0664

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

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

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