rs367327

Variant names:

• chr14-87945603-T-C
• rs367327
• NM_000153.4:c.1620A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000153.4(GALC):​c.1620A>G​(p.Thr540Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,609,970 control chromosomes in the GnomAD database, including 791,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70143 hom., cov: 31)
  • Exomes 𝑓: 0.99 (720877 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.81
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 14-87945603-T-C is Benign according to our data. Variant chr14-87945603-T-C is described in ClinVar as Benign. ClinVar VariationId is 167118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.81 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.1620A>G	p.Thr540Thr	synonymous	Exon 14 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1551A>G	p.Thr517Thr	synonymous	Exon 13 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1542A>G	p.Thr514Thr	synonymous	Exon 14 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.1620A>G	p.Thr540Thr	synonymous	Exon 14 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1581A>G	p.Thr527Thr	synonymous	Exon 13 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1554A>G	p.Thr518Thr	synonymous	Exon 14 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.959 AC: 145664 AN: 151938 Hom.: 70104 Cov.: 31

Gnomad AFR AF: 0.866

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: 0.964

GnomAD2 exomes AF: 0.985 AC: 245232 AN: 248934 AF XY: 0.988

Gnomad AFR exome AF: 0.863

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: 0.992

GnomAD4 exome AF: 0.994 AC: 1449420 AN: 1457914 Hom.: 720877 Cov.: 39 AF XY: 0.995 AC XY: 721779 AN XY: 725526

African (AFR) AF: 0.859 AC: 28614 AN: 33312

American (AMR) AF: 0.991 AC: 44248 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 26013 AN: 26058

East Asian (EAS) AF: 0.953 AC: 37815 AN: 39674

South Asian (SAS) AF: 0.997 AC: 85980 AN: 86198

European-Finnish (FIN) AF: 1.00 AC: 53390 AN: 53390

Middle Eastern (MID) AF: 0.991 AC: 5701 AN: 5754

European-Non Finnish (NFE) AF: 1.00 AC: 1108306 AN: 1108700

Other (OTH) AF: 0.986 AC: 59353 AN: 60192

GnomAD4 genome AF: 0.959 AC: 145763 AN: 152056 Hom.: 70143 Cov.: 31 AF XY: 0.960 AC XY: 71334 AN XY: 74332

African (AFR) AF: 0.866 AC: 35927 AN: 41492

American (AMR) AF: 0.984 AC: 15007 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3465 AN: 3472

East Asian (EAS) AF: 0.938 AC: 4817 AN: 5136

South Asian (SAS) AF: 0.995 AC: 4797 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

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

European-Non Finnish (NFE) AF: 0.999 AC: 67884 AN: 67944

Other (OTH) AF: 0.965 AC: 2039 AN: 2114

Alfa AF: 0.985 Hom.: 101894

Bravo AF: 0.952

Asia WGS AF: 0.961 AC: 3342 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
-	-	3	Galactosylceramide beta-galactosidase deficiency (3)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.36
DANN	Benign	0.30
PhyloP100		-2.8
Mutation Taster		=66/34	polymorphism

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: rs367327; hg19: chr14-88411947; COSMIC: COSV108090171;