14-87934869-T-C

Variant names:

• chr14-87934869-T-C
• rs421262
• NM_000153.4:c.1921A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• 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
• Publications: 39 publications found

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 Gene-Disease associations (from GenCC):

• Krabbe disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -17 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• 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 VariationId is 92500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.1921A>G	p.Thr641Ala	missense_variant	Exon 17 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.1921A>G	p.Thr641Ala	missense_variant	Exon 17 of 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

GnomAD2 exomes AF: 0.985 AC: 243168 AN: 246956 AF XY: 0.988

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 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

African (AFR) AF: 0.854 AC: 28450 AN: 33330

American (AMR) AF: 0.991 AC: 44173 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 26003 AN: 26048

East Asian (EAS) AF: 0.953 AC: 37799 AN: 39658

South Asian (SAS) AF: 0.997 AC: 85958 AN: 86176

European-Finnish (FIN) AF: 1.00 AC: 53364 AN: 53364

Middle Eastern (MID) AF: 0.990 AC: 5691 AN: 5746

European-Non Finnish (NFE) AF: 1.00 AC: 1107686 AN: 1108132

Other (OTH) AF: 0.986 AC: 59352 AN: 60214

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

African (AFR) AF: 0.861 AC: 35725 AN: 41490

American (AMR) AF: 0.984 AC: 15014 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3463 AN: 3470

East Asian (EAS) AF: 0.937 AC: 4813 AN: 5134

South Asian (SAS) AF: 0.995 AC: 4801 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10608 AN: 10608

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67933 AN: 67996

Other (OTH) AF: 0.963 AC: 2032 AN: 2110

Alfa AF: 0.985 Hom.: 148892

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

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27638593, 24078576, 27884173, 20981092, 10477434) -

May 16, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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
PhyloP100		0.66
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
Mutation Taster		=97/3	polymorphism (auto)

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: rs421262; hg19: chr14-88401213; COSMIC: COSV107205313;