Genetic Variant GALC:c.1834+20_1834+22dupTTT (chr14-87941372-T-TAAA) – 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+20_1834+22dupTTT 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 0.000027 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00027 ( 1 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: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

GALC links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.1834+20_1834+22dupTTT		intron_variant	Intron 15 of 16	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 link	c.1834+22_1834+23insTTT		intron_variant	Intron 15 of 16	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes

AF:

0.0000272

AC:

AN:

146952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000203

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

GnomAD2 exomes

AF:

0.000233

AC:

AN:

167536

AF XY:

0.000218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000375

Gnomad ASJ exome

AF:

0.000290

Gnomad EAS exome

AF:

0.000160

Gnomad FIN exome

AF:

0.000496

Gnomad NFE exome

AF:

0.000215

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000272

AC:

307

AN:

1127578

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

137

AN XY:

571518

show subpopulations

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

African (AFR)

AF:

0.000511

AC:

AN:

25442

American (AMR)

AF:

0.000188

AC:

AN:

37178

Ashkenazi Jewish (ASJ)

AF:

0.000181

AC:

AN:

22056

East Asian (EAS)

AF:

0.000316

AC:

AN:

34856

South Asian (SAS)

AF:

0.000150

AC:

AN:

73246

European-Finnish (FIN)

AF:

0.000234

AC:

AN:

42734

Middle Eastern (MID)

AF:

0.000209

AC:

AN:

4782

European-Non Finnish (NFE)

AF:

0.000261

AC:

219

AN:

839300

Other (OTH)

AF:

0.000646

AC:

AN:

47984

⚠️ 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: 0.254

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0000272

AC:

AN:

146952

Hom.:

Cov.:

AF XY:

0.0000281

AC XY:

AN XY:

71250

show subpopulations

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

African (AFR)

AF:

0.0000252

AC:

AN:

39734

American (AMR)

AF:

0.000203

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:

0.00

AC:

AN:

66714

Other (OTH)

AF:

0.00

AC:

AN:

2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0522941), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

978

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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-TAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over