rs74073730

Variant names:

• chr14-87963473-G-A
• rs74073730
• NM_000153.4:c.1072C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-87963473-G-A
• chr14-87963473-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.1072C>T​(p.Leu358Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00299 in 1,612,984 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (68 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (65 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.04
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 14-87963473-G-A is Benign according to our data. Variant chr14-87963473-G-A is described in ClinVar as Benign. ClinVar VariationId is 314751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0557 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.1072C>T	p.Leu358Leu	synonymous	Exon 10 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1003C>T	p.Leu335Leu	synonymous	Exon 9 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.994C>T	p.Leu332Leu	synonymous	Exon 10 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.1072C>T	p.Leu358Leu	synonymous	Exon 10 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.1060C>T	p.Leu354Leu	synonymous	Exon 10 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.1062C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2517 AN: 151920 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00604

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00395 AC: 983 AN: 249108 AF XY: 0.00305

Gnomad AFR exome AF: 0.0557

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00158 AC: 2304 AN: 1460946 Hom.: 65 Cov.: 31 AF XY: 0.00135 AC XY: 979 AN XY: 726794

African (AFR) AF: 0.0561 AC: 1877 AN: 33436

American (AMR) AF: 0.00318 AC: 142 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5762

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111276

Other (OTH) AF: 0.00341 AC: 206 AN: 60356

GnomAD4 genome AF: 0.0166 AC: 2523 AN: 152038 Hom.: 68 Cov.: 32 AF XY: 0.0160 AC XY: 1189 AN XY: 74324

African (AFR) AF: 0.0576 AC: 2388 AN: 41438

American (AMR) AF: 0.00603 AC: 92 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68002

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00303 Hom.: 24

Bravo AF: 0.0185

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Galactosylceramide beta-galactosidase deficiency (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.4
DANN	Benign	0.76
PhyloP100		4.0
Mutation Taster		=90/10	polymorphism

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: rs74073730; hg19: chr14-88429817;