rs2440199

chr8-96144183-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001001557.4(GDF6):c.*380A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 223,256 control chromosomes in the GnomAD database, including 45,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.65 (33295 hom., cov: 25)
  • Exomes 𝑓: 0.53 (11828 hom.)
• Consequence: GDF6 NM_001001557.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.947

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-96144183-T-C is Benign according to our data. Variant chr8-96144183-T-C is described in ClinVar as [Benign]. Clinvar id is 364023.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF6	NM_001001557.4	c.*380A>G		3_prime_UTR_variant	2/2	ENST00000287020.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF6	ENST00000287020.7	c.*380A>G		3_prime_UTR_variant	2/2	1	NM_001001557.4	P1

Frequencies

GnomAD3 genomes AF: 0.650 AC: 96667 AN: 148784 Hom.: 33242 Cov.: 25

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.626

GnomAD4 exome AF: 0.533 AC: 39650 AN: 74346 Hom.: 11828 Cov.: 0 AF XY: 0.534 AC XY: 21008 AN XY: 39324

Gnomad4 AFR exome AF: 0.862

Gnomad4 AMR exome AF: 0.379

Gnomad4 ASJ exome AF: 0.591

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.546

Gnomad4 FIN exome AF: 0.499

Gnomad4 NFE exome AF: 0.557

Gnomad4 OTH exome AF: 0.557

GnomAD4 genome AF: 0.650 AC: 96779 AN: 148910 Hom.: 33295 Cov.: 25 AF XY: 0.643 AC XY: 46531 AN XY: 72334

Gnomad4 AFR AF: 0.877

Gnomad4 AMR AF: 0.471

Gnomad4 ASJ AF: 0.642

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.552

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.629

Alfa AF: 0.631 Hom.: 3903

Bravo AF: 0.644

Asia WGS AF: 0.451 AC: 1566 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.94
Dann	Benign	0.51

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: rs2440199; hg19: chr8-97156411;