Genetic Variant NM_000153.4:c.1834+22delT (chr14-87941372-TA-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000153.4(GALC):c.1834+22delT 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 0.00046 ( 0 hom., cov: 0)

Exomes 𝑓: 0.033 ( 2 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: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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+22delT	intron	N/A	NP_000144.2	P54803-1
GALC	NM_001201401.2		c.1765+22delT	intron	N/A	NP_001188330.1	P54803-3
GALC	NM_001201402.2		c.1756+22delT	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+22delT	intron	N/A	ENSP00000261304.2	P54803-1
GALC	ENST00000921945.1		c.1795+22delT	intron	N/A	ENSP00000592004.1
GALC	ENST00000950382.1		c.1768+22delT	intron	N/A	ENSP00000620441.1

Frequencies

GnomAD3 genomes

AF:

0.000463

AC:

AN:

146848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000504

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000814

Gnomad ASJ

AF:

0.000583

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000428

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.000225

Gnomad OTH

AF:

0.000500

GnomAD2 exomes

AF:

0.0310

AC:

5197

AN:

167536

AF XY:

0.0306

show subpopulations

Gnomad AFR exome

AF:

0.0713

Gnomad AMR exome

AF:

0.0219

Gnomad ASJ exome

AF:

0.0433

Gnomad EAS exome

AF:

0.00967

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.0317

Gnomad OTH exome

AF:

0.0337

GnomAD4 exome

AF:

0.0327

AC:

35355

AN:

1080020

Hom.:

Cov.:

AF XY:

0.0321

AC XY:

17529

AN XY:

546218

show subpopulations

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

African (AFR)

AF:

0.0758

AC:

1732

AN:

22842

American (AMR)

AF:

0.0196

AC:

702

AN:

35880

Ashkenazi Jewish (ASJ)

AF:

0.0355

AC:

736

AN:

20708

East Asian (EAS)

AF:

0.00725

AC:

248

AN:

34210

South Asian (SAS)

AF:

0.0251

AC:

1739

AN:

69394

European-Finnish (FIN)

AF:

0.0299

AC:

1212

AN:

40482

Middle Eastern (MID)

AF:

0.0202

AC:

AN:

4596

European-Non Finnish (NFE)

AF:

0.0340

AC:

27371

AN:

806210

Other (OTH)

AF:

0.0333

AC:

1522

AN:

45698

⚠️ 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: 0.266

Heterozygous variant carriers

3854

7709

11563

15418

19272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1030

2060

3090

4120

5150

<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:

0.000463

AC:

AN:

146896

Hom.:

Cov.:

AF XY:

0.000393

AC XY:

AN XY:

71260

show subpopulations

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

African (AFR)

AF:

0.000502

AC:

AN:

39804

American (AMR)

AF:

0.000813

AC:

AN:

14760

Ashkenazi Jewish (ASJ)

AF:

0.000583

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

4996

South Asian (SAS)

AF:

0.000430

AC:

AN:

4654

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

9404

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000225

AC:

AN:

66650

Other (OTH)

AF:

0.000497

AC:

AN:

2012

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.318

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:

0.0353

Hom.:

978

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.26

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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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