rs3213918

Variant names:

• chr14-87949881-G-A
• rs3213918
• NM_000153.4:c.1302C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-87949881-G-A
• chr14-87949881-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000153.4(GALC):​c.1302C>T​(p.Ser434Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,598,544 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S434S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (91 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.36
• Publications: 7 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=-0.73).
• BP6: Variant 14-87949881-G-A is Benign according to our data. Variant chr14-87949881-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00746 (1134/151950) while in subpopulation EAS AF = 0.0432 (222/5134). AF 95% confidence interval is 0.0386. There are 17 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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.1302C>T	p.Ser434Ser	synonymous	Exon 12 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1233C>T	p.Ser411Ser	synonymous	Exon 11 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1224C>T	p.Ser408Ser	synonymous	Exon 12 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.1302C>T	p.Ser434Ser	synonymous	Exon 12 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1263C>T	p.Ser421Ser	synonymous	Exon 11 of 16	ENSP00000592004.1
	GALC	ENST00000393568.8	TSL:2	c.1233C>T	p.Ser411Ser	synonymous	Exon 11 of 16	ENSP00000377198.4	P54803-3

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1137 AN: 151832 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00809

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0435

Gnomad SAS AF: 0.0307

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00872 AC: 2167 AN: 248572 AF XY: 0.00907

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0387

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00682

GnomAD4 exome AF: 0.00493 AC: 7136 AN: 1446594 Hom.: 91 Cov.: 26 AF XY: 0.00547 AC XY: 3945 AN XY: 720584

African (AFR) AF: 0.0125 AC: 414 AN: 33030

American (AMR) AF: 0.00590 AC: 263 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.000308 AC: 8 AN: 25962

East Asian (EAS) AF: 0.0359 AC: 1416 AN: 39464

South Asian (SAS) AF: 0.0236 AC: 2022 AN: 85818

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53290

Middle Eastern (MID) AF: 0.0112 AC: 63 AN: 5646

European-Non Finnish (NFE) AF: 0.00220 AC: 2419 AN: 1099060

Other (OTH) AF: 0.00886 AC: 529 AN: 59732

GnomAD4 genome AF: 0.00746 AC: 1134 AN: 151950 Hom.: 17 Cov.: 32 AF XY: 0.00765 AC XY: 568 AN XY: 74270

African (AFR) AF: 0.0111 AC: 459 AN: 41476

American (AMR) AF: 0.00808 AC: 123 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0432 AC: 222 AN: 5134

South Asian (SAS) AF: 0.0305 AC: 147 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00222 AC: 151 AN: 67920

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00825

Asia WGS AF: 0.0310 AC: 107 AN: 3476

EpiCase AF: 0.00268

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs3213918; hg19: chr14-88416225; COSMIC: COSV54324035; COSMIC: COSV54324035;