rs2440199

Variant names:

• chr8-96144183-T-C
• rs2440199
• NM_001001557.4:c.*380A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.947
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Klippel-Feil syndrome 1, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microphthalmia

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• multiple synostoses syndrome 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• isolated Klippel-Feil syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated microphthalmia 4

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis 17

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 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 CliVar as Benign. Clinvar id is 364023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF6	NM_001001557.4	c.*380A>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000287020.7	NP_001001557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7	c.*380A>G		3_prime_UTR_variant	Exon 2 of 2	1	NM_001001557.4	ENSP00000287020.4

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

African (AFR) AF: 0.862 AC: 1570 AN: 1822

American (AMR) AF: 0.379 AC: 1572 AN: 4150

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 1043 AN: 1764

East Asian (EAS) AF: 0.221 AC: 859 AN: 3888

South Asian (SAS) AF: 0.546 AC: 6034 AN: 11042

European-Finnish (FIN) AF: 0.499 AC: 1710 AN: 3424

Middle Eastern (MID) AF: 0.580 AC: 160 AN: 276

European-Non Finnish (NFE) AF: 0.557 AC: 24504 AN: 44032

Other (OTH) AF: 0.557 AC: 2198 AN: 3948

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

African (AFR) AF: 0.877 AC: 35423 AN: 40404

American (AMR) AF: 0.471 AC: 6957 AN: 14780

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2221 AN: 3458

East Asian (EAS) AF: 0.276 AC: 1367 AN: 4948

South Asian (SAS) AF: 0.591 AC: 2776 AN: 4696

European-Finnish (FIN) AF: 0.552 AC: 5438 AN: 9860

Middle Eastern (MID) AF: 0.695 AC: 196 AN: 282

European-Non Finnish (NFE) AF: 0.602 AC: 40632 AN: 67518

Other (OTH) AF: 0.629 AC: 1295 AN: 2060

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Klippel-Feil syndrome 1, autosomal dominant Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.94
DANN	Benign	0.51
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2440199; hg19: chr8-97156411;