NM_000153.4:c.42G>C

Variant names:

• chr14-87993123-C-G
• rs112992946
• NM_000153.4:c.42G>C

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.42G>C​(p.Ala14Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,586,138 control chromosomes in the GnomAD database, including 16,698 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. A14A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1114 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15584 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0380
• Publications: 15 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=-0.74).
• BP6: Variant 14-87993123-C-G is Benign according to our data. Variant chr14-87993123-C-G is described in ClinVar as Benign. ClinVar VariationId is 92505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.038 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.152 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.42G>C	p.Ala14Ala	synonymous	Exon 1 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.42G>C	p.Ala14Ala	synonymous	Exon 1 of 16	NP_001188330.1	P54803-3
	GALC	NM_001424072.1		c.-229G>C		5_prime_UTR	Exon 1 of 18	NP_001411001.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.42G>C	p.Ala14Ala	synonymous	Exon 1 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.30G>C	p.Ala10Ala	synonymous	Exon 1 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.32G>C		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17033 AN: 152168 Hom.: 1111 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0945

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.117 AC: 22335 AN: 190218 AF XY: 0.116

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.000810

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.142 AC: 204126 AN: 1433858 Hom.: 15584 Cov.: 33 AF XY: 0.141 AC XY: 100162 AN XY: 710602

African (AFR) AF: 0.0342 AC: 1130 AN: 33044

American (AMR) AF: 0.140 AC: 5697 AN: 40790

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3008 AN: 25656

East Asian (EAS) AF: 0.00125 AC: 48 AN: 38420

South Asian (SAS) AF: 0.101 AC: 8319 AN: 82774

European-Finnish (FIN) AF: 0.158 AC: 7773 AN: 49094

Middle Eastern (MID) AF: 0.160 AC: 904 AN: 5660

European-Non Finnish (NFE) AF: 0.154 AC: 169452 AN: 1099142

Other (OTH) AF: 0.131 AC: 7795 AN: 59278

GnomAD4 genome AF: 0.112 AC: 17042 AN: 152280 Hom.: 1114 Cov.: 33 AF XY: 0.112 AC XY: 8368 AN XY: 74462

African (AFR) AF: 0.0396 AC: 1647 AN: 41556

American (AMR) AF: 0.130 AC: 1994 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5174

South Asian (SAS) AF: 0.0944 AC: 456 AN: 4830

European-Finnish (FIN) AF: 0.154 AC: 1638 AN: 10618

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.154 AC: 10492 AN: 68006

Other (OTH) AF: 0.108 AC: 228 AN: 2116

Alfa AF: 0.118 Hom.: 448

Bravo AF: 0.106

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Galactosylceramide beta-galactosidase deficiency (4)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.1
DANN	Benign	0.73
PhyloP100		-0.038
PromoterAI		-0.055	Neutral
Mutation Taster		=100/0	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: rs112992946; hg19: chr14-88459467;