Genetic Variant GALC:c.1834+19_1834+22dupTTTT (chr14-87941372-T-TAAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_000153.4(GALC):c.1834+19_1834+22dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GALC
NM_000153.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.263

Publications

2 publications found

Variant links:

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

GALC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GALC	NM_000153.4	MANE Select	c.1834+19_1834+22dupTTTT	intron	N/A	NP_000144.2	P54803-1
GALC	NM_001201401.2		c.1765+19_1765+22dupTTTT	intron	N/A	NP_001188330.1	P54803-3
GALC	NM_001201402.2		c.1756+19_1756+22dupTTTT	intron	N/A	NP_001188331.1	P54803-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GALC	ENST00000261304.7	TSL:1 MANE Select	c.1834+22_1834+23insTTTT	intron	N/A	ENSP00000261304.2	P54803-1
GALC	ENST00000921945.1		c.1795+22_1795+23insTTTT	intron	N/A	ENSP00000592004.1
GALC	ENST00000950382.1		c.1768+22_1768+23insTTTT	intron	N/A	ENSP00000620441.1

Frequencies

GnomAD3 genomes

AF:

0.00000680

AC:

AN:

146954

Hom.:

Cov.:

show subpopulations

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000115

AC:

AN:

1129370

Hom.:

Cov.:

AF XY:

0.00000874

AC XY:

AN XY:

572394

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25458

American (AMR)

AF:

0.0000537

AC:

AN:

37218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22084

East Asian (EAS)

AF:

0.00

AC:

AN:

34932

South Asian (SAS)

AF:

0.0000136

AC:

AN:

73324

European-Finnish (FIN)

AF:

0.0000234

AC:

AN:

42770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4784

European-Non Finnish (NFE)

AF:

0.00000952

AC:

AN:

840726

Other (OTH)

AF:

0.0000208

AC:

AN:

48074

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.260

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000680

AC:

AN:

146954

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71250

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39734

American (AMR)

AF:

0.00

AC:

AN:

14746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5010

South Asian (SAS)

AF:

0.00

AC:

AN:

4672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66716

Other (OTH)

AF:

0.00

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

978

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.26

Splicing

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

Publications

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14-87941372-TAAA-TAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over