rs74887188

chr14-87965625-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BA1

The NM_000153.4(GALC):c.913A>G(p.Ile305Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,613,152 control chromosomes in the GnomAD database, including 283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I305I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (252 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.92

Genes affected

GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000153.4
• BP6: Variant 14-87965625-T-C is Benign according to our data. Variant chr14-87965625-T-C is described in ClinVar as [Benign]. Clinvar id is 198993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965625-T-C is described in Lovd as [Benign]. Variant chr14-87965625-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.913A>G	p.Ile305Val	missense_variant	9/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.913A>G	p.Ile305Val	missense_variant	9/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152074 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00806 AC: 2004 AN: 248704 Hom.: 105 AF XY: 0.00749 AC XY: 1011 AN XY: 134912

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0992

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.000746

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00357 AC: 5219 AN: 1460960 Hom.: 252 Cov.: 32 AF XY: 0.00355 AC XY: 2583 AN XY: 726788

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.00269

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.000295

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.00386 AC: 588 AN: 152192 Hom.: 31 Cov.: 33 AF XY: 0.00464 AC XY: 345 AN XY: 74408

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00470 Hom.: 67

Bravo AF: 0.00492

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000538 AC: 2

ESP6500EA AF: 0.000609 AC: 5

ExAC AF: 0.00799 AC: 965

Asia WGS AF: 0.0370 AC: 128 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 14, 2014

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2021

This variant is associated with the following publications: (PMID: Wenger[Review], 33191329, 21228398, 24252386, 27638593, 28552323, 9272171, 16607461, 30323943) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0070	D;D;T;T
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.91	P;D;D;.
Vest4		0.59
MVP		0.96
MPC		0.32
ClinPred		0.035	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74887188; hg19: chr14-88431969; COSMIC: COSV54324049; COSMIC: COSV54324049;