rs959842362

Variant names:

• chr17-75758572-C-A
• rs959842362
• NM_000154.2:c.821G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-75758572-C-A
• chr17-75758572-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000154.2(GALK1):​c.821G>T​(p.Gly274Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. G274D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALK1 NM_000154.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12
• Publications: 2 publications found

Genes affected

GALK1 (HGNC:4118): (galactokinase 1) Galactokinase is a major enzyme for the metabolism of galactose and its deficiency causes congenital cataracts during infancy and presenile cataracts in the adult population. [provided by RefSeq, Jul 2008]

GALK1 Gene-Disease associations (from GenCC):

• galactokinase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000154.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06727132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALK1	NM_000154.2	c.821G>T	p.Gly274Val	missense_variant	Exon 6 of 8	ENST00000588479.6	NP_000145.1
GALK1	NM_001381985.1	c.821G>T	p.Gly274Val	missense_variant	Exon 6 of 9		NP_001368914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALK1	ENST00000588479.6	c.821G>T	p.Gly274Val	missense_variant	Exon 6 of 8	1	NM_000154.2	ENSP00000465930.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444414 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 718548

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 84978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109736

Other (OTH) AF: 0.00 AC: 0 AN: 60002

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.24	T;.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.76	.;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-2.9	N;.;N
PhyloP100		2.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.9	N;.;.
REVEL	Benign	0.15
Sift	Benign	0.66	T;.;.
Sift4G	Benign	0.93	T;T;T
Polyphen		0.020	B;.;B
Vest4		0.23
MutPred		0.41		Loss of ubiquitination at K272 (P = 0.063);.;Loss of ubiquitination at K272 (P = 0.063);
MVP		0.75
MPC		0.21
ClinPred		0.42	T
GERP RS		2.5
Varity_R		0.14
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs959842362; hg19: chr17-73754653;