NM_001001557.4:c.*1978G>A

Variant names:

• chr8-96142585-C-T
• rs112542818
• NM_001001557.4:c.*1978G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The NM_001001557.4(GDF6):​c.*1978G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00421 in 152,628 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: GDF6 NM_001001557.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.90
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14).
• BP6: Variant 8-96142585-C-T is Benign according to our data. Variant chr8-96142585-C-T is described in ClinVar as [Benign]. Clinvar id is 913596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 641 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF6	NM_001001557.4	c.*1978G>A		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.*1978G>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_001001557.4	ENSP00000287020.4

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 641 AN: 152078 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00231 AC: 1 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.00385 AC XY: 1 AN XY: 260

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: 0.00235 AC: 1 AN: 426

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: 0.00421 AC: 641 AN: 152196 Hom.: 2 Cov.: 33 AF XY: 0.00413 AC XY: 307 AN XY: 74402

African (AFR) AF: 0.00113 AC: 47 AN: 41514

American (AMR) AF: 0.00334 AC: 51 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4820

European-Finnish (FIN) AF: 0.00293 AC: 31 AN: 10582

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68014

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00267 Hom.: 1

Bravo AF: 0.00393

Asia WGS AF: 0.00289 AC: 10 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	-0.14
CADD	Benign	18
DANN	Benign	0.93
PhyloP100		6.9
Mutation Taster		=100/0	polymorphism

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: rs112542818; hg19: chr8-97154813;