8-96145173-T-G

Variant names:

• chr8-96145173-T-G
• rs121909355
• NM_001001557.4:c.758A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001557.4(GDF6):​c.758A>C​(p.Gln253Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,347,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q253H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GDF6 NM_001001557.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16971451).

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.758A>C	p.Gln253Pro	missense	Exon 2 of 2	NP_001001557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF6	ENST00000287020.7	TSL:1 MANE Select	c.758A>C	p.Gln253Pro	missense	Exon 2 of 2	ENSP00000287020.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1347364 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 664470

African (AFR) AF: 0.00 AC: 0 AN: 27588

American (AMR) AF: 0.00 AC: 0 AN: 31776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23606

East Asian (EAS) AF: 0.00 AC: 0 AN: 32014

South Asian (SAS) AF: 0.00 AC: 0 AN: 74980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4268

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1064184

Other (OTH) AF: 0.00 AC: 0 AN: 56060

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.28
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.047
Sift	Benign	0.31	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.41		Gain of catalytic residue at P252 (P = 0.0186)
MVP		0.50
MPC		0.98
ClinPred		0.078	T
GERP RS		-0.55
Varity_R		0.11
gMVP		0.44
Mutation Taster		=56/44	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: rs121909355; hg19: chr8-97157401;