8-96142562-T-C

Position:

• chr8-96142562-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000287020.7(GDF6):​c.*2001A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0701 in 152,694 control chromosomes in the GnomAD database, including 466 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (465 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1 hom.)
• Consequence: GDF6 ENST00000287020.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.32

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 -16 ACMG points.

• BP6: Variant 8-96142562-T-C is Benign according to our data. Variant chr8-96142562-T-C is described in ClinVar as [Benign]. Clinvar id is 364010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF6	NM_001001557.4	c.*2001A>G		3_prime_UTR_variant	2/2	ENST00000287020.7	NP_001001557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7	c.*2001A>G		3_prime_UTR_variant	2/2	1	NM_001001557.4	ENSP00000287020	P1

Frequencies

GnomAD3 genomes AF: 0.0701 AC: 10672 AN: 152150 Hom.: 464 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0838

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0689

GnomAD4 exome AF: 0.0446 AC: 19 AN: 426 Hom.: 1 Cov.: 0 AF XY: 0.0472 AC XY: 12 AN XY: 254

Gnomad4 FIN exome AF: 0.0452

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0702 AC: 10686 AN: 152268 Hom.: 465 Cov.: 33 AF XY: 0.0666 AC XY: 4961 AN XY: 74466

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0429

Gnomad4 ASJ AF: 0.0838

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0257

Gnomad4 FIN AF: 0.0482

Gnomad4 NFE AF: 0.0656

Gnomad4 OTH AF: 0.0682

Alfa AF: 0.0693 Hom.: 109

Bravo AF: 0.0734

Asia WGS AF: 0.0150 AC: 51 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	16
DANN	Benign	0.91

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: rs36028712; hg19: chr8-97154790;