rs2255182

Variant names:

• chr8-96152676-A-G
• rs2255182
• NM_001001557.4:c.407-7152T>C

Variant summary

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

The NM_001001557.4(GDF6):​c.407-7152T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 152,064 control chromosomes in the GnomAD database, including 15,730 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 0.45 (15730 hom., cov: 32)
• Consequence: GDF6 NM_001001557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001557.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF6	NM_001001557.4	MANE Select	c.407-7152T>C		intron	N/A	NP_001001557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF6	ENST00000287020.7	TSL:1 MANE Select	c.407-7152T>C		intron	N/A	ENSP00000287020.4

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68124 AN: 151944 Hom.: 15724 Cov.: 32

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.431

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

GnomAD4 genome AF: 0.448 AC: 68179 AN: 152064 Hom.: 15730 Cov.: 32 AF XY: 0.446 AC XY: 33130 AN XY: 74332

African (AFR) AF: 0.387 AC: 16063 AN: 41472

American (AMR) AF: 0.359 AC: 5489 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1673 AN: 3464

East Asian (EAS) AF: 0.274 AC: 1419 AN: 5170

South Asian (SAS) AF: 0.471 AC: 2270 AN: 4820

European-Finnish (FIN) AF: 0.484 AC: 5113 AN: 10558

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34649 AN: 67968

Other (OTH) AF: 0.436 AC: 921 AN: 2114

Alfa AF: 0.481 Hom.: 33017

Bravo AF: 0.431

Asia WGS AF: 0.373 AC: 1296 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.038
DANN	Benign	0.32
PhyloP100		-2.4
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: rs2255182; hg19: chr8-97164904;