rs73997615

chr17-75758116-G-Achr17-75758116-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000154.2(GALK1):c.1119C>T(p.Gly373=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,612,686 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (9 hom.)
• Consequence: GALK1 NM_000154.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.90

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-75758116-G-A is Benign according to our data. Variant chr17-75758116-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 459629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75758116-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00232 (353/152320) while in subpopulation AMR AF= 0.00438 (67/15310). AF 95% confidence interval is 0.00354. There are 0 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALK1	NM_000154.2	c.1119C>T	p.Gly373=	synonymous_variant	8/8	ENST00000588479.6
GALK1	NM_001381985.1	c.1119C>T	p.Gly373=	synonymous_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALK1	ENST00000588479.6	c.1119C>T	p.Gly373=	synonymous_variant	8/8	1	NM_000154.2	P1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00213 AC: 527 AN: 246894 Hom.: 4 AF XY: 0.00197 AC XY: 265 AN XY: 134286

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00127 AC: 1860 AN: 1460366 Hom.: 9 Cov.: 32 AF XY: 0.00131 AC XY: 949 AN XY: 726466

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.000780

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74476

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00287 Hom.: 2

Bravo AF: 0.00304

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of galactokinase Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	- -

Junctional epidermolysis bullosa with pyloric atresia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.27
Dann	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs73997615; hg19: chr17-73754197; COSMIC: COSV52325976; COSMIC: COSV52325976;