dbSNP rs191767015: GALC:c.195+10A>G (chr14-87992960-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000153.4(GALC):c.195+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,512,872 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

GALC
NM_000153.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.90

Publications

1 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 14-87992960-T-C is Benign according to our data. Variant chr14-87992960-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 456716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00604 (920/152230) while in subpopulation AFR AF = 0.0212 (883/41562). AF 95% confidence interval is 0.0201. There are 13 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 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.195+10A>G	intron	N/A	NP_000144.2	P54803-1
GALC	NM_001201401.2		c.195+10A>G	intron	N/A	NP_001188330.1	P54803-3
GALC	NM_001201402.2		c.117+423A>G	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.195+10A>G	intron	N/A	ENSP00000261304.2	P54803-1
GALC	ENST00000622264.4	TSL:1	c.183+10A>G	intron	N/A	ENSP00000480649.1	A0A087WX10
GALC	ENST00000474294.6	TSL:1	n.185+10A>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00603

AC:

917

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.000118

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000392

AC:

AN:

117494

AF XY:

0.000227

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.000341

Gnomad ASJ exome

AF:

0.000559

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000634

Gnomad OTH exome

AF:

0.000299

GnomAD4 exome

AF:

0.000575

AC:

783

AN:

1360642

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

336

AN XY:

672246

show subpopulations

African (AFR)

AF:

0.0238

AC:

654

AN:

27500

American (AMR)

AF:

0.000716

AC:

AN:

34906

Ashkenazi Jewish (ASJ)

AF:

0.000460

AC:

AN:

23908

East Asian (EAS)

AF:

0.00

AC:

AN:

31844

South Asian (SAS)

AF:

0.0000260

AC:

AN:

76790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34064

Middle Eastern (MID)

AF:

0.00151

AC:

AN:

3976

European-Non Finnish (NFE)

AF:

0.0000233

AC:

AN:

1071270

Other (OTH)

AF:

0.00106

AC:

AN:

56384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

130

173

216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00604

AC:

920

AN:

152230

Hom.:

Cov.:

AF XY:

0.00587

AC XY:

437

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0212

AC:

883

AN:

41562

American (AMR)

AF:

0.00144

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67974

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

131

174

218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00450

Hom.:

Bravo

AF:

0.00699

Asia WGS

AF:

0.00116

AC:

AN:

3470

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Galactosylceramide beta-galactosidase deficiency (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

4.3

(source)

DANN

Benign

0.35

PhyloP100

-1.9

PromoterAI

0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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