14-87993090-G-T

Variant names:

• chr14-87993090-G-T
• rs111976362
• NM_000153.4:c.75C>A

Variant summary

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

The ENST00000261304.7(GALC):​c.75C>A​(p.Gly25Gly) 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 1,576,980 control chromosomes in the GnomAD database, including 16,523 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. G25G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1110 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15413 hom.)
• Consequence: GALC ENST00000261304.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.684
• Publications: 13 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: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 14-87993090-G-T is Benign according to our data. Variant chr14-87993090-G-T is described in ClinVar as Benign. ClinVar VariationId is 92510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.684 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: ENST00000261304.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.75C>A	p.Gly25Gly	synonymous	Exon 1 of 17	NP_000144.2
	GALC	NM_001201401.2		c.75C>A	p.Gly25Gly	synonymous	Exon 1 of 16	NP_001188330.1
	GALC	NR_187582.1		n.93C>A		non_coding_transcript_exon	Exon 1 of 16

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.75C>A	p.Gly25Gly	synonymous	Exon 1 of 17	ENSP00000261304.2
	GALC	ENST00000622264.4	TSL:1	c.63C>A	p.Gly21Gly	synonymous	Exon 1 of 10	ENSP00000480649.1
	GALC	ENST00000474294.6	TSL:1	n.65C>A		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17002 AN: 152046 Hom.: 1107 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0947

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.111 AC: 19648 AN: 176728 AF XY: 0.110

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.000697

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.142 AC: 202099 AN: 1424824 Hom.: 15413 Cov.: 33 AF XY: 0.140 AC XY: 99017 AN XY: 705636

African (AFR) AF: 0.0341 AC: 1121 AN: 32878

American (AMR) AF: 0.138 AC: 5512 AN: 39990

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2975 AN: 25466

East Asian (EAS) AF: 0.00123 AC: 47 AN: 38302

South Asian (SAS) AF: 0.0997 AC: 8183 AN: 82108

European-Finnish (FIN) AF: 0.156 AC: 7475 AN: 47778

Middle Eastern (MID) AF: 0.169 AC: 800 AN: 4742

European-Non Finnish (NFE) AF: 0.154 AC: 168289 AN: 1094684

Other (OTH) AF: 0.131 AC: 7697 AN: 58876

GnomAD4 genome AF: 0.112 AC: 17011 AN: 152156 Hom.: 1110 Cov.: 33 AF XY: 0.112 AC XY: 8339 AN XY: 74364

African (AFR) AF: 0.0396 AC: 1648 AN: 41568

American (AMR) AF: 0.130 AC: 1993 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3466

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5162

South Asian (SAS) AF: 0.0945 AC: 456 AN: 4824

European-Finnish (FIN) AF: 0.154 AC: 1632 AN: 10600

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

European-Non Finnish (NFE) AF: 0.154 AC: 10469 AN: 67930

Other (OTH) AF: 0.108 AC: 228 AN: 2108

Alfa AF: 0.0945 Hom.: 338

Bravo AF: 0.105

Asia WGS AF: 0.0530 AC: 184 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.54
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		0.68
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs111976362; hg19: chr14-88459434; COSMIC: COSV54324266; COSMIC: COSV54324266;