6-38702981-G-T

Variant names:

• chr6-38702981-G-T
• rs759126965
• NM_006708.3:c.74C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006708.3(GLO1):​c.74C>A​(p.Pro25His) variant causes a missense change. The variant allele was found at a frequency of 0.000000703 in 1,422,394 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P25R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GLO1 NM_006708.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.64
• Publications: 0 publications found

Genes affected

GLO1 (HGNC:4323): (glyoxalase I) The enzyme encoded by this gene is responsible for the catalysis and formation of S-lactoyl-glutathione from methylglyoxal condensation and reduced glutatione. Glyoxalase I is linked to HLA and is localized to 6p21.3-p21.1, between HLA and the centromere. [provided by RefSeq, Jul 2008]

ENSG00000298390 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006708.3. 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
	GLO1	NM_006708.3	MANE Select	c.74C>A	p.Pro25His	missense	Exon 1 of 6	NP_006699.2	Q04760-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLO1	ENST00000373365.5	TSL:1 MANE Select	c.74C>A	p.Pro25His	missense	Exon 1 of 6	ENSP00000362463.3	Q04760-1
	GLO1	ENST00000887179.1		c.74C>A	p.Pro25His	missense	Exon 1 of 7	ENSP00000557238.1
	GLO1	ENST00000887178.1		c.74C>A	p.Pro25His	missense	Exon 1 of 6	ENSP00000557237.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422394 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 710108

⚠️ 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: 32404

American (AMR) AF: 0.00 AC: 0 AN: 44258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 85474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077988

Other (OTH) AF: 0.00 AC: 0 AN: 59034

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0053	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.97	D
Vest4		0.51
MutPred		0.22		Gain of catalytic residue at P25 (P = 0.0289)
MVP		0.43
MPC		0.39
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.51
Mutation Taster		=45/55	disease causing

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: rs759126965; hg19: chr6-38670757;