NM_000153.4:c.1350C>T

Variant names:

• chr14-87947867-G-A
• rs398076
• NM_000153.4:c.1350C>T

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.1350C>T​(p.Ser450Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,610,008 control chromosomes in the GnomAD database, including 126,114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12159 hom., cov: 31)
  • Exomes 𝑓: 0.39 (113955 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.109
• Publications: 33 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=-0.79).
• BP6: Variant 14-87947867-G-A is Benign according to our data. Variant chr14-87947867-G-A is described in ClinVar as Benign. ClinVar VariationId is 92494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.109 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 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.1350C>T	p.Ser450Ser	synonymous	Exon 13 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1281C>T	p.Ser427Ser	synonymous	Exon 12 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1272C>T	p.Ser424Ser	synonymous	Exon 13 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.1350C>T	p.Ser450Ser	synonymous	Exon 13 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1311C>T	p.Ser437Ser	synonymous	Exon 12 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1284C>T	p.Ser428Ser	synonymous	Exon 13 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60115 AN: 151636 Hom.: 12146 Cov.: 31

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.395

GnomAD2 exomes AF: 0.368 AC: 91227 AN: 248096 AF XY: 0.372

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.392 AC: 571804 AN: 1458254 Hom.: 113955 Cov.: 35 AF XY: 0.393 AC XY: 284890 AN XY: 725544

African (AFR) AF: 0.435 AC: 14494 AN: 33322

American (AMR) AF: 0.281 AC: 12518 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10793 AN: 26064

East Asian (EAS) AF: 0.194 AC: 7686 AN: 39630

South Asian (SAS) AF: 0.385 AC: 33156 AN: 86202

European-Finnish (FIN) AF: 0.399 AC: 21312 AN: 53358

Middle Eastern (MID) AF: 0.383 AC: 2204 AN: 5752

European-Non Finnish (NFE) AF: 0.402 AC: 446430 AN: 1109190

Other (OTH) AF: 0.386 AC: 23211 AN: 60192

GnomAD4 genome AF: 0.396 AC: 60162 AN: 151754 Hom.: 12159 Cov.: 31 AF XY: 0.394 AC XY: 29204 AN XY: 74144

African (AFR) AF: 0.431 AC: 17830 AN: 41346

American (AMR) AF: 0.340 AC: 5172 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1469 AN: 3468

East Asian (EAS) AF: 0.186 AC: 953 AN: 5128

South Asian (SAS) AF: 0.392 AC: 1889 AN: 4818

European-Finnish (FIN) AF: 0.412 AC: 4352 AN: 10562

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27133 AN: 67884

Other (OTH) AF: 0.401 AC: 846 AN: 2110

Alfa AF: 0.395 Hom.: 37166

Bravo AF: 0.390

Asia WGS AF: 0.369 AC: 1283 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.384

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Galactosylceramide beta-galactosidase deficiency (5)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.4
DANN	Benign	0.61
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs398076; hg19: chr14-88414211; COSMIC: COSV54324856; COSMIC: COSV54324856;