chr17-75758228-G-C

Variant names:

• chr17-75758228-G-C
• rs200502537
• NM_000154.2:c.1089C>G

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.1089C>G​(p.His363Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H363H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GALK1 NM_000154.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• Publications: 1 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, 7 uncertain in NM_000154.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038729876).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000154.2. 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
	GALK1	NM_000154.2	MANE Select	c.1089C>G	p.His363Gln	missense	Exon 7 of 8	NP_000145.1
	GALK1	NM_001381985.1		c.1089C>G	p.His363Gln	missense	Exon 7 of 9	NP_001368914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALK1	ENST00000588479.6	TSL:1 MANE Select	c.1089C>G	p.His363Gln	missense	Exon 7 of 8	ENSP00000465930.1
	GALK1	ENST00000225614.6	TSL:2	c.1089C>G	p.His363Gln	missense	Exon 7 of 9	ENSP00000225614.1
	GALK1	ENST00000592997.6	TSL:2	c.999C>G	p.His333Gln	missense	Exon 7 of 8	ENSP00000464765.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000884 AC: 2 AN: 226136 AF XY: 0.00000808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452400 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 721942

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 43296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25844

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39398

South Asian (SAS) AF: 0.00 AC: 0 AN: 85238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108654

Other (OTH) AF: 0.00 AC: 0 AN: 60004

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000834 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.0010
DANN	Benign	0.74
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-1.9
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.89	N
REVEL	Benign	0.15
Sift	Benign	0.59	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.29		Loss of catalytic residue at M365 (P = 0.0644)
MVP		0.82
MPC		0.16
ClinPred		0.022	T
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.39

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: rs200502537; hg19: chr17-73754309;