chr14-87993147-G-A

Variant names:

• chr14-87993147-G-A
• rs886038260
• NM_000153.4:c.18C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000153.4(GALC):​c.18C>T​(p.Leu6Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,431,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L6L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.560
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP7: Synonymous conserved (PhyloP=-0.56 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.18C>T	p.Leu6Leu	synonymous	Exon 1 of 17	NP_000144.2
	GALC	NM_001201401.2		c.18C>T	p.Leu6Leu	synonymous	Exon 1 of 16	NP_001188330.1
	GALC	NR_187582.1		n.36C>T		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.18C>T	p.Leu6Leu	synonymous	Exon 1 of 17	ENSP00000261304.2
	GALC	ENST00000622264.4	TSL:1	c.6C>T	p.Leu2Leu	synonymous	Exon 1 of 10	ENSP00000480649.1
	GALC	ENST00000474294.6	TSL:1	n.8C>T		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1431724 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 709402

African (AFR) AF: 0.00 AC: 0 AN: 32976

American (AMR) AF: 0.00 AC: 0 AN: 40138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25644

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38160

South Asian (SAS) AF: 0.00 AC: 0 AN: 82510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098230

Other (OTH) AF: 0.00 AC: 0 AN: 59276

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.77
PhyloP100		-0.56
PromoterAI		0.19	Neutral

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: rs886038260; hg19: chr14-88459491;