NM_000154.2:c.1031C>T

Variant names:

• chr17-75758286-G-A
• rs371517491
• NM_000154.2:c.1031C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000154.2(GALK1):​c.1031C>T​(p.Thr344Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,591,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: GALK1 NM_000154.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 17-75758286-G-A is Pathogenic according to our data. Variant chr17-75758286-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALK1	NM_000154.2	c.1031C>T	p.Thr344Met	missense_variant	Exon 7 of 8	ENST00000588479.6	NP_000145.1
GALK1	NM_001381985.1	c.1031C>T	p.Thr344Met	missense_variant	Exon 7 of 9		NP_001368914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALK1	ENST00000588479.6	c.1031C>T	p.Thr344Met	missense_variant	Exon 7 of 8	1	NM_000154.2	ENSP00000465930.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000146 AC: 3 AN: 205992 Hom.: 0 AF XY: 0.0000178 AC XY: 2 AN XY: 112078

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000653

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.0000215 AC: 31 AN: 1439060 Hom.: 0 Cov.: 34 AF XY: 0.0000154 AC XY: 11 AN XY: 714026

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.0000239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000182

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000768 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of galactokinase Pathogenic:6

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 25, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GALK1 c.1031C>T (p.Thr344Met) results in a non-conservative amino acid change located in the GHMP kinase, C-terminal domain (IPR013750) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.5e-05 in 205992 control chromosomes. c.1031C>T has been reported in the literature in at-least three Japanese individuals affected with Deficiency Of Galactokinase (example, Asada_1999). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal GALK enzyme activity in patient erythrocytes as well as in an in-vitro COS cell expression system. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.0	M;.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.037	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.94
MVP		0.98
MPC		0.69
ClinPred		0.90	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs371517491; hg19: chr17-73754367; COSMIC: COSV99563471; COSMIC: COSV99563471;