chr14-87941372-TAA-T

Variant names:

• chr14-87941372-TAA-T
• rs34752717
• NM_000153.4:c.1834+21_1834+22delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000153.4(GALC):​c.1834+21_1834+22delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,273,312 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.484
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

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.1834+21_1834+22delTT		intron	N/A	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1765+21_1765+22delTT		intron	N/A	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1756+21_1756+22delTT		intron	N/A	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.1834+21_1834+22delTT		intron	N/A	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1795+21_1795+22delTT		intron	N/A	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1768+21_1768+22delTT		intron	N/A	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 146946 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000678

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000143 AC: 24 AN: 167536 AF XY: 0.000142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000125

Gnomad ASJ exome AF: 0.000436

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000578

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.000253

GnomAD4 exome AF: 0.000284 AC: 320 AN: 1126366 Hom.: 0 AF XY: 0.000252 AC XY: 144 AN XY: 570984

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000553 AC: 14 AN: 25316

American (AMR) AF: 0.0000807 AC: 3 AN: 37166

Ashkenazi Jewish (ASJ) AF: 0.000318 AC: 7 AN: 22030

East Asian (EAS) AF: 0.00 AC: 0 AN: 34918

South Asian (SAS) AF: 0.000109 AC: 8 AN: 73250

European-Finnish (FIN) AF: 0.000234 AC: 10 AN: 42680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4780

European-Non Finnish (NFE) AF: 0.000324 AC: 272 AN: 838290

Other (OTH) AF: 0.000125 AC: 6 AN: 47936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 146946 Hom.: 0 Cov.: 0 AF XY: 0.0000281 AC XY: 2 AN XY: 71246

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 39730

American (AMR) AF: 0.0000678 AC: 1 AN: 14746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 5010

South Asian (SAS) AF: 0.00 AC: 0 AN: 4672

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66714

Other (OTH) AF: 0.00 AC: 0 AN: 2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00114 Hom.: 978

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34752717; hg19: chr14-88407716; COSMIC: COSV54330143; COSMIC: COSV54330143;