chr3-129288884-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/20 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020187.3. 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
	HMCES	NM_020187.3	MANE Select	c.214C>T	p.Pro72Ser	missense	Exon 3 of 7	NP_064572.2	Q96FZ2
	HMCES	NM_001006109.1		c.214C>T	p.Pro72Ser	missense	Exon 3 of 7	NP_001006109.1	Q96FZ2
	HMCES	NM_001370343.1		c.214C>T	p.Pro72Ser	missense	Exon 3 of 7	NP_001357272.1	Q96FZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMCES	ENST00000383463.9	TSL:1 MANE Select	c.214C>T	p.Pro72Ser	missense	Exon 3 of 7	ENSP00000372955.3	Q96FZ2
	HMCES	ENST00000389735.7	TSL:1	c.214C>T	p.Pro72Ser	missense	Exon 3 of 7	ENSP00000374385.3	Q96FZ2
	HMCES	ENST00000502878.6	TSL:1	c.214C>T	p.Pro72Ser	missense	Exon 3 of 7	ENSP00000426215.1	Q96FZ2

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

African (AFR) AF: 0.00 AC: 0 AN: 33158

American (AMR) AF: 0.00 AC: 0 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 39218

South Asian (SAS) AF: 0.00 AC: 0 AN: 84380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000641 AC: 7 AN: 1092506

Other (OTH) AF: 0.00 AC: 0 AN: 59160

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N
PhyloP100		1.1
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.26
Sift	Benign	0.17	T
Sift4G	Benign	0.34	T
Polyphen		0.051	B
Vest4		0.19
MutPred		0.52		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
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs375669857; hg19: chr3-129007727;