rs34752717

Variant names:

• chr14-87941372-TAAA-T
• rs34752717
• NM_000153.4:c.1834+20_1834+22delTTT

Your query was ambiguous. Multiple possible variants found:

• chr14-87941372-TAAA-T
• chr14-87941372-TAAA-TA
• chr14-87941372-TAAA-TAA
• chr14-87941372-TAAA-TAAAA
• chr14-87941372-TAAA-TAAAAA
• chr14-87941372-TAAA-TAAAAAA
• chr14-87941372-TAAA-TAAAAAAA
• chr14-87941372-TAAA-TAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000153.4(GALC):​c.1834+20_1834+22delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 1,129,352 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 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000089 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• 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: 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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+20_1834+22delTTT		intron	N/A	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1765+20_1765+22delTTT		intron	N/A	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1756+20_1756+22delTTT		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+20_1834+22delTTT		intron	N/A	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1795+20_1795+22delTTT		intron	N/A	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1768+20_1768+22delTTT		intron	N/A	ENSP00000620441.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 146952 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000885 AC: 10 AN: 1129352 Hom.: 0 AF XY: 0.00000699 AC XY: 4 AN XY: 572386

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

African (AFR) AF: 0.00 AC: 0 AN: 25456

American (AMR) AF: 0.00 AC: 0 AN: 37222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22084

East Asian (EAS) AF: 0.00 AC: 0 AN: 34934

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4784

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 840718

Other (OTH) AF: 0.00 AC: 0 AN: 48070

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 146952 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 71248

African (AFR) AF: 0.00 AC: 0 AN: 39732

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 9432

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66716

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;