rs36028712

Variant names:

• chr8-96142562-T-C
• rs36028712
• NM_001001557.4:c.*2001A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001001557.4(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.070 (465 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1 hom.)
• Consequence: GDF6 NM_001001557.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.32
• Publications: 5 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 -8 ACMG points.

• 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 rank	MANE	Protein	UniProt
GDF6	NM_001001557.4	c.*2001A>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.*2001A>G		3_prime_UTR_variant	Exon 2 of 2	1	NM_001001557.4	ENSP00000287020.4

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0452 AC: 19 AN: 420

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.105 AC: 4366 AN: 41534

American (AMR) AF: 0.0429 AC: 657 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 291 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4824

European-Finnish (FIN) AF: 0.0482 AC: 511 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0656 AC: 4459 AN: 68020

Other (OTH) AF: 0.0682 AC: 144 AN: 2112

Alfa AF: 0.0710 Hom.: 183

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

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	Uncertain	-0.080
CADD	Benign	16
DANN	Benign	0.91
PhyloP100		5.3
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: rs36028712; hg19: chr8-97154790;