3-129288972-C-T

Variant names:

• chr3-129288972-C-T
• rs779979711
• NM_020187.3:c.302C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020187.3(HMCES):​c.302C>T​(p.Thr101Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,428,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T101N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HMCES NM_020187.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

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.302C>T	p.Thr101Ile	missense	Exon 3 of 7	NP_064572.2	Q96FZ2
	HMCES	NM_001006109.1		c.302C>T	p.Thr101Ile	missense	Exon 3 of 7	NP_001006109.1	Q96FZ2
	HMCES	NM_001370343.1		c.302C>T	p.Thr101Ile	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.302C>T	p.Thr101Ile	missense	Exon 3 of 7	ENSP00000372955.3	Q96FZ2
	HMCES	ENST00000389735.7	TSL:1	c.302C>T	p.Thr101Ile	missense	Exon 3 of 7	ENSP00000374385.3	Q96FZ2
	HMCES	ENST00000502878.6	TSL:1	c.302C>T	p.Thr101Ile	missense	Exon 3 of 7	ENSP00000426215.1	Q96FZ2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428034 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 706880

African (AFR) AF: 0.00 AC: 0 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25456

East Asian (EAS) AF: 0.00 AC: 0 AN: 39108

South Asian (SAS) AF: 0.00 AC: 0 AN: 83294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1086088

Other (OTH) AF: 0.00 AC: 0 AN: 58578

GnomAD4 genome Cov.: 32

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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.0
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.029	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.75		Loss of disorder (P = 0.0255)
MVP		0.70
MPC		0.61
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.71
gMVP		0.69
Mutation Taster		=41/59	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: rs779979711; hg19: chr3-129007815; COSMIC: COSV104702024;