14-87992951-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000153.4(GALC):​c.195+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,509,366 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0032 ( 14 hom. )

Consequence

GALC
NM_000153.4 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0400
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 14-87992951-C-T is Benign according to our data. Variant chr14-87992951-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87992951-C-T is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GALCNM_000153.4 linkuse as main transcriptc.195+19G>A intron_variant ENST00000261304.7 NP_000144.2 P54803-1A0A0A0MQV0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GALCENST00000261304.7 linkuse as main transcriptc.195+19G>A intron_variant 1 NM_000153.4 ENSP00000261304.2 P54803-1

Frequencies

GnomAD3 genomes
AF:
0.00195
AC:
297
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000603
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00371
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.00167
AC:
190
AN:
113460
Hom.:
2
AF XY:
0.00165
AC XY:
105
AN XY:
63670
show subpopulations
Gnomad AFR exome
AF:
0.00146
Gnomad AMR exome
AF:
0.00144
Gnomad ASJ exome
AF:
0.000422
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000248
Gnomad FIN exome
AF:
0.000690
Gnomad NFE exome
AF:
0.00296
Gnomad OTH exome
AF:
0.00275
GnomAD4 exome
AF:
0.00318
AC:
4322
AN:
1357082
Hom.:
14
Cov.:
33
AF XY:
0.00309
AC XY:
2068
AN XY:
670198
show subpopulations
Gnomad4 AFR exome
AF:
0.000548
Gnomad4 AMR exome
AF:
0.00157
Gnomad4 ASJ exome
AF:
0.000587
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000327
Gnomad4 FIN exome
AF:
0.000624
Gnomad4 NFE exome
AF:
0.00373
Gnomad4 OTH exome
AF:
0.00361
GnomAD4 genome
AF:
0.00195
AC:
297
AN:
152284
Hom.:
0
Cov.:
33
AF XY:
0.00149
AC XY:
111
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.000601
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.00371
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00325
Hom.:
1
Bravo
AF:
0.00203
Asia WGS
AF:
0.000289
AC:
1
AN:
3470

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 18, 2020Variant summary: GALC c.195+19G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0017 in 113460 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in GALC causing Krabbe Disease phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.195+19G>A in individuals affected with Krabbe Disease and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Galactosylceramide beta-galactosidase deficiency Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 05, 2021- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 18, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
CADD
Benign
7.1
DANN
Benign
0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs189853941; hg19: chr14-88459295; API