rs185943390

Variant names:

• chr14-87993491-C-A
• rs185943390
• NM_001201402.2:c.9G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-87993491-C-A
• chr14-87993491-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001201402.2(GALC):​c.9G>T​(p.Gly3Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,535,102 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: GALC NM_001201402.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.259
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-87993491-C-A is Benign according to our data. Variant chr14-87993491-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374669.
• BP7: Synonymous conserved (PhyloP=-0.259 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001201402.2. 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_001201402.2		c.9G>T	p.Gly3Gly	synonymous	Exon 1 of 17	NP_001188331.1	P54803-4
	GALC	NM_001424076.1		c.-581G>T		5_prime_UTR	Exon 1 of 18	NP_001411005.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000393569.6	TSL:2	c.9G>T	p.Gly3Gly	synonymous	Exon 1 of 17	ENSP00000377199.2	P54803-4

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00130 AC: 170 AN: 130812 AF XY: 0.00133

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.000864

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00146 AC: 2025 AN: 1382794 Hom.: 3 Cov.: 31 AF XY: 0.00158 AC XY: 1075 AN XY: 682338

African (AFR) AF: 0.0000950 AC: 3 AN: 31586

American (AMR) AF: 0.00126 AC: 45 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.000675 AC: 17 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35842

South Asian (SAS) AF: 0.00120 AC: 95 AN: 79220

European-Finnish (FIN) AF: 0.00117 AC: 39 AN: 33468

Middle Eastern (MID) AF: 0.00351 AC: 20 AN: 5694

European-Non Finnish (NFE) AF: 0.00160 AC: 1723 AN: 1078220

Other (OTH) AF: 0.00143 AC: 83 AN: 57886

GnomAD4 genome AF: 0.00119 AC: 182 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74472

African (AFR) AF: 0.000192 AC: 8 AN: 41576

American (AMR) AF: 0.00196 AC: 30 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00179 AC: 122 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00152

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Galactosylceramide beta-galactosidase deficiency (2)
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.73
PhyloP100		-0.26
PromoterAI		-0.010	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs185943390; hg19: chr14-88459835;