rs421466

Variant names:

• chr14-87941531-T-A
• rs421466
• NM_000153.4:c.1698A>T

Your query was ambiguous. Multiple possible variants found:

• chr14-87941531-T-A
• chr14-87941531-T-C
• chr14-87941531-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000153.4(GALC):​c.1698A>T​(p.Val566Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,588,716 control chromosomes in the GnomAD database, including 780,039 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. V566V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.96 (69954 hom., cov: 33)
  • Exomes 𝑓: 0.99 (710085 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.00900
• Publications: 22 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: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 14-87941531-T-A is Benign according to our data. Variant chr14-87941531-T-A is described in ClinVar as Benign. ClinVar VariationId is 92498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.009 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000153.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.1698A>T	p.Val566Val	synonymous	Exon 15 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1629A>T	p.Val543Val	synonymous	Exon 14 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1620A>T	p.Val540Val	synonymous	Exon 15 of 17	NP_001188331.1	P54803-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.1698A>T	p.Val566Val	synonymous	Exon 15 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1659A>T	p.Val553Val	synonymous	Exon 14 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1632A>T	p.Val544Val	synonymous	Exon 15 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.957 AC: 145443 AN: 151930 Hom.: 69914 Cov.: 33

Gnomad AFR AF: 0.861

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 0.938

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: 244906 AN: 248700 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: 0.999

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.994 AC: 1427972 AN: 1436668 Hom.: 710085 Cov.: 32 AF XY: 0.995 AC XY: 712611 AN XY: 716452

African (AFR) AF: 0.853 AC: 27980 AN: 32800

American (AMR) AF: 0.991 AC: 44185 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 25841 AN: 25884

East Asian (EAS) AF: 0.953 AC: 37681 AN: 39530

South Asian (SAS) AF: 0.997 AC: 85494 AN: 85712

European-Finnish (FIN) AF: 1.00 AC: 53376 AN: 53376

Middle Eastern (MID) AF: 0.990 AC: 5653 AN: 5708

European-Non Finnish (NFE) AF: 1.00 AC: 1089128 AN: 1089586

Other (OTH) AF: 0.986 AC: 58634 AN: 59484

GnomAD4 genome AF: 0.957 AC: 145543 AN: 152048 Hom.: 69954 Cov.: 33 AF XY: 0.958 AC XY: 71209 AN XY: 74316

African (AFR) AF: 0.861 AC: 35721 AN: 41488

American (AMR) AF: 0.984 AC: 15001 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3461 AN: 3468

East Asian (EAS) AF: 0.938 AC: 4812 AN: 5132

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

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

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

European-Non Finnish (NFE) AF: 0.999 AC: 67880 AN: 67940

Other (OTH) AF: 0.963 AC: 2038 AN: 2116

Alfa AF: 0.979 Hom.: 18296

Bravo AF: 0.950

Asia WGS AF: 0.960 AC: 3340 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Galactosylceramide beta-galactosidase deficiency (5)
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	GALC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.4
DANN	Benign	0.61
PhyloP100		-0.0090
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs421466; hg19: chr14-88407875; COSMIC: COSV108090170;