3-129279761-C-T

Variant names:

• chr3-129279761-C-T
• rs1313109323
• NM_020187.3:c.29C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020187.3(HMCES):​c.29C>T​(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMCES NM_020187.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

Genes affected

HMCES (HGNC:24446): (5-hydroxymethylcytosine binding, ES cell specific) Enables single-stranded DNA binding activity. Involved in cellular response to DNA damage stimulus and protein-DNA covalent cross-linking. Located in replication fork. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMCES	NM_020187.3	c.29C>T	p.Pro10Leu	missense_variant	Exon 2 of 7	ENST00000383463.9	NP_064572.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMCES	ENST00000383463.9	c.29C>T	p.Pro10Leu	missense_variant	Exon 2 of 7	1	NM_020187.3	ENSP00000372955.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249820 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135140

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29C>T (p.P10L) alteration is located in exon 2 (coding exon 1) of the HMCES gene. This alteration results from a C to T substitution at nucleotide position 29, causing the proline (P) at amino acid position 10 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;.;T;T;T;.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.049
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	T;.;T;T;.;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	2.9	.;M;.;.;M;M;.;.
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.013	D;D;D;T;D;D;D;T
Sift4G	Uncertain	0.042	D;T;D;T;T;T;T;T
Polyphen		0.99, 0.97	.;D;D;.;D;D;.;.
Vest4		0.28, 0.31, 0.28
MutPred		0.57		Gain of glycosylation at T15 (P = 0.0058);Gain of glycosylation at T15 (P = 0.0058);Gain of glycosylation at T15 (P = 0.0058);Gain of glycosylation at T15 (P = 0.0058);Gain of glycosylation at T15 (P = 0.0058);Gain of glycosylation at T15 (P = 0.0058);Gain of glycosylation at T15 (P = 0.0058);Gain of glycosylation at T15 (P = 0.0058);
MVP		0.54
MPC		0.22
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.43
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1313109323; hg19: chr3-128998604;