3-129288884-C-T

Variant names:

• chr3-129288884-C-T
• rs375669857
• NM_020187.3:c.214C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020187.3(HMCES):​c.214C>T​(p.Pro72Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000487 in 1,437,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P72T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: HMCES NM_020187.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25201643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMCES	NM_020187.3	c.214C>T	p.Pro72Ser	missense_variant	Exon 3 of 7	ENST00000383463.9	NP_064572.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMCES	ENST00000383463.9	c.214C>T	p.Pro72Ser	missense_variant	Exon 3 of 7	1	NM_020187.3	ENSP00000372955.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000487 AC: 7 AN: 1437026 Hom.: 0 Cov.: 30 AF XY: 0.00000562 AC XY: 4 AN XY: 711950

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000641

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.214C>T (p.P72S) alteration is located in exon 3 (coding exon 2) of the HMCES gene. This alteration results from a C to T substitution at nucleotide position 214, causing the proline (P) at amino acid position 72 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	.;D;.;D;D
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N;.;N;N;.
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.26
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.051	B;B;B;B;.
Vest4		0.19
MutPred		0.52		Gain of MoRF binding (P = 0.065);Gain of MoRF binding (P = 0.065);Gain of MoRF binding (P = 0.065);Gain of MoRF binding (P = 0.065);Gain of MoRF binding (P = 0.065);
MVP		0.42
MPC		0.16
ClinPred		0.55	D
GERP RS		2.8
Varity_R		0.47
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375669857; hg19: chr3-129007727;