rs41274865

Variant names:

• chr9-34647805-G-C
• rs41274865
• NM_000155.4:c.378-27G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000155.4(GALT):​c.378-27G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,614,114 control chromosomes in the GnomAD database, including 3,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.047 (261 hom., cov: 32)
  • Exomes 𝑓: 0.061 (2932 hom.)
• Consequence: GALT NM_000155.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.55

Genes affected

GALT (HGNC:4135): (galactose-1-phosphate uridylyltransferase) Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ENSG00000258728 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-34647805-G-C is Benign according to our data. Variant chr9-34647805-G-C is described in ClinVar as [Benign]. Clinvar id is 25166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALT	NM_000155.4	c.378-27G>C		intron_variant	Intron 4 of 10	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.51-27G>C		intron_variant	Intron 2 of 8		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.378-27G>C		intron_variant	Intron 4 of 10	1	NM_000155.4	ENSP00000368119.4
ENSG00000258728	ENST00000556278.1	c.253-310G>C		intron_variant	Intron 2 of 7	5		ENSP00000451792.1

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7137 AN: 152136 Hom.: 260 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.00946

Gnomad SAS AF: 0.0687

Gnomad FIN AF: 0.0672

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0642

Gnomad OTH AF: 0.0441

GnomAD3 exomes AF: 0.0543 AC: 13652 AN: 251492 Hom.: 439 AF XY: 0.0565 AC XY: 7675 AN XY: 135922

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0473

Gnomad ASJ exome AF: 0.0512

Gnomad EAS exome AF: 0.00870

Gnomad SAS exome AF: 0.0754

Gnomad FIN exome AF: 0.0687

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0613 AC: 89600 AN: 1461860 Hom.: 2932 Cov.: 33 AF XY: 0.0618 AC XY: 44978 AN XY: 727232

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0481

Gnomad4 ASJ exome AF: 0.0512

Gnomad4 EAS exome AF: 0.00645

Gnomad4 SAS exome AF: 0.0755

Gnomad4 FIN exome AF: 0.0678

Gnomad4 NFE exome AF: 0.0644

Gnomad4 OTH exome AF: 0.0582

GnomAD4 genome AF: 0.0469 AC: 7139 AN: 152254 Hom.: 261 Cov.: 32 AF XY: 0.0467 AC XY: 3475 AN XY: 74432

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0488

Gnomad4 ASJ AF: 0.0481

Gnomad4 EAS AF: 0.00928

Gnomad4 SAS AF: 0.0685

Gnomad4 FIN AF: 0.0672

Gnomad4 NFE AF: 0.0642

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0549 Hom.: 51

Bravo AF: 0.0421

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 06, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Galactosemia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.5
DANN	Benign	0.43
BranchPoint Hunter		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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

Other links and lift over

dbSNP: rs41274865; hg19: chr9-34647802; COSMIC: COSV66592691; COSMIC: COSV66592691;