8-96157099-C-A

Variant names:

• chr8-96157099-C-A
• rs2514527
• NM_001001557.4:c.406+3188G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001001557.4(GDF6):​c.406+3188G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 152,096 control chromosomes in the GnomAD database, including 31,696 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (31696 hom., cov: 33)
• Consequence: GDF6 NM_001001557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF6	NM_001001557.4	c.406+3188G>T		intron_variant	Intron 1 of 1	ENST00000287020.7	NP_001001557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7	c.406+3188G>T		intron_variant	Intron 1 of 1	1	NM_001001557.4	ENSP00000287020.4

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96193 AN: 151978 Hom.: 31656 Cov.: 33

Gnomad AFR AF: 0.772

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.620

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.633 AC: 96286 AN: 152096 Hom.: 31696 Cov.: 33 AF XY: 0.625 AC XY: 46448 AN XY: 74352

African (AFR) AF: 0.773 AC: 32069 AN: 41498

American (AMR) AF: 0.468 AC: 7157 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2351 AN: 3468

East Asian (EAS) AF: 0.263 AC: 1360 AN: 5168

South Asian (SAS) AF: 0.608 AC: 2932 AN: 4820

European-Finnish (FIN) AF: 0.558 AC: 5897 AN: 10560

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42402 AN: 67974

Other (OTH) AF: 0.620 AC: 1312 AN: 2116

Alfa AF: 0.626 Hom.: 115809

Bravo AF: 0.627

Asia WGS AF: 0.443 AC: 1545 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.71
DANN	Benign	0.62
PhyloP100		-0.29
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: rs2514527; hg19: chr8-97169327;