14-87934869-T-C

Position:

• chr14-87934869-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.1921A>G​(p.Thr641Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,609,350 control chromosomes in the GnomAD database, including 790,270 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (69977 hom., cov: 31)
  • Exomes 𝑓: 0.99 (720293 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.659

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]

GALC (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.753622E-7).
• BP6: Variant 14-87934869-T-C is Benign according to our data. Variant chr14-87934869-T-C is described in ClinVar as [Benign]. Clinvar id is 92500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87934869-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.1921A>G	p.Thr641Ala	missense_variant	17/17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.1921A>G	p.Thr641Ala	missense_variant	17/17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes AF: 0.957 AC: 145494 AN: 151984 Hom.: 69937 Cov.: 31

Gnomad AFR AF: 0.861

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.994

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.962

GnomAD3 exomes AF: 0.985 AC: 243168 AN: 246956 Hom.: 119870 AF XY: 0.988 AC XY: 132487 AN XY: 134106

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 0.939

Gnomad SAS exome AF: 0.997

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.994 AC: 1448476 AN: 1457248 Hom.: 720293 Cov.: 36 AF XY: 0.995 AC XY: 721390 AN XY: 725246

Gnomad4 AFR exome AF: 0.854

Gnomad4 AMR exome AF: 0.991

Gnomad4 ASJ exome AF: 0.998

Gnomad4 EAS exome AF: 0.953

Gnomad4 SAS exome AF: 0.997

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.986

GnomAD4 genome AF: 0.957 AC: 145594 AN: 152102 Hom.: 69977 Cov.: 31 AF XY: 0.958 AC XY: 71238 AN XY: 74350

Gnomad4 AFR AF: 0.861

Gnomad4 AMR AF: 0.984

Gnomad4 ASJ AF: 0.998

Gnomad4 EAS AF: 0.937

Gnomad4 SAS AF: 0.995

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.963

Alfa AF: 0.991 Hom.: 116757

Bravo AF: 0.950

TwinsUK AF: 0.999 AC: 3706

ALSPAC AF: 0.999 AC: 3852

ESP6500AA AF: 0.872 AC: 3290

ESP6500EA AF: 0.999 AC: 8241

ExAC AF: 0.983 AC: 118661

Asia WGS AF: 0.960 AC: 3340 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27638593, 24078576, 27884173, 20981092, 10477434) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2016	Variant summary: The GALC c.1921A>G (p.Thr641Ala) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to isoform mismatch). This variant was found in 118335/120404 control chromosomes (58239 homozygotes) at a frequency of 0.9828162, which is approximately 440 times the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361), highly suggesting this variant is a benign polymorphism and the ancestral allele. The variant has been found to co-occur in Krabbe Disease patients with compound heterozygous pathogenic variants that would explain the patients phenotype. In addition, a clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as Benign. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.13
DANN	Benign	0.15
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.035	T;T;T
MetaRNN	Benign	9.8e-7	T;T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.4	N;N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Vest4		0.014
MPC		0.12
ClinPred		0.00033	T
GERP RS		-3.1
Varity_R		0.028
gMVP		0.60

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: rs421262; hg19: chr14-88401213;