17-75758563-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000154.2(GALK1):c.830G>A(p.Arg277Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,596,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R277W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: GALK1 NM_000154.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.38

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000154.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALK1	NM_000154.2	c.830G>A	p.Arg277Gln	missense_variant	6/8	ENST00000588479.6
GALK1	NM_001381985.1	c.830G>A	p.Arg277Gln	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALK1	ENST00000588479.6	c.830G>A	p.Arg277Gln	missense_variant	6/8	1	NM_000154.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000453 AC: 10 AN: 220888 Hom.: 0 AF XY: 0.0000654 AC XY: 8 AN XY: 122374

Gnomad AFR exome AF: 0.000523

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000174

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 24 AN: 1444418 Hom.: 0 Cov.: 34 AF XY: 0.0000167 AC XY: 12 AN XY: 718476

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.0000667

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74496

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000464 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000667 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 05, 2022

Variant summary: GALK1 c.830G>A (p.Arg277Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 220888 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GALK1 causing Deficiency Of Galactokinase (4.5e-05 vs 0.0011), allowing no conclusion about variant significance. c.830G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Deficiency Of Galactokinase (example, Doo Park_2007). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (example, Doo Park_2007). The most pronounced variant effect results in approximately 10%-15% of normal GALK activity in vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Deficiency of galactokinase Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0090	D;.;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.98
MVP		0.98
MPC		0.73
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.85
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: rs370029131; hg19: chr17-73754644;