2-38666166-C-T

Variant names:

• chr2-38666166-C-T
• rs1159501195
• NM_138801.3:c.5C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_138801.3(GALM):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GALM NM_138801.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51
• Publications: 0 publications found

Genes affected

GALM (HGNC:24063): (galactose mutarotase) This gene encodes an enzyme that catalyzes the epimerization of hexose sugars such as glucose and galactose. The encoded protein is expressed in the cytoplasm and has a preference for galactose. The encoded protein may be required for normal galactose metabolism by maintaining the equilibrium of alpha and beta anomers of galactose.[provided by RefSeq, Mar 2009]

GALM Gene-Disease associations (from GenCC):

• galactosemia 4

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

GALM-AS1 (HGNC:41037):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0727061).
• BP6: Variant 2-38666166-C-T is Benign according to our data. Variant chr2-38666166-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3098041.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138801.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALM	NM_138801.3	MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 7	NP_620156.1	A0A384MDW6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALM	ENST00000272252.10	TSL:1 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 1 of 7	ENSP00000272252.5	Q96C23
	GALM	ENST00000862593.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 8	ENSP00000532652.1
	GALM	ENST00000862591.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 7	ENSP00000532650.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247136 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458428 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725442

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

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 85840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110126

Other (OTH) AF: 0.00 AC: 0 AN: 60242

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.3
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.35	N
PhyloP100		1.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.024
Sift	Benign	0.63	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.28		Gain of sheet (P = 0.0827)
MVP		0.16
MPC		0.051
ClinPred		0.044	T
GERP RS		1.7
PromoterAI		-0.025	Neutral
Varity_R		0.076
gMVP		0.30
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1159501195; hg19: chr2-38893308;