X-101884261-T-C

Variant names:

• chrX-101884261-T-C
• rs372963755
• NM_001394560.1:c.1337A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394560.1(ZMAT1):​c.1337A>G​(p.Tyr446Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. 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. Y446S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: ZMAT1 NM_001394560.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.591
• Publications: 0 publications found

Genes affected

ZMAT1 (HGNC:29377): (zinc finger matrin-type 1) This gene encodes a protein containing Cys2-His2 (C2H2)-type zinc fingers, which are similar to those found in the nuclear matrix protein matrin 3. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

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=0.19739482).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394560.1. 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
	ZMAT1	NM_001394560.1	MANE Select	c.1337A>G	p.Tyr446Cys	missense	Exon 6 of 6	NP_001381489.1	Q5H9K5-3
	ZMAT1	NM_001011657.4		c.1166A>G	p.Tyr389Cys	missense	Exon 7 of 7	NP_001011657.2	Q5H9K5-1
	ZMAT1	NM_001282400.2		c.653A>G	p.Tyr218Cys	missense	Exon 10 of 10	NP_001269329.1	Q5H9K5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMAT1	ENST00000651725.2	MANE Select	c.1337A>G	p.Tyr446Cys	missense	Exon 6 of 6	ENSP00000498446.1	Q5H9K5-3
	ZMAT1	ENST00000372782.4	TSL:1	c.1166A>G	p.Tyr389Cys	missense	Exon 7 of 7	ENSP00000361868.3	Q5H9K5-1
	ZMAT1	ENST00000878190.1		c.1406A>G	p.Tyr469Cys	missense	Exon 7 of 7	ENSP00000548249.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097742 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363336

African (AFR) AF: 0.00 AC: 0 AN: 26369

American (AMR) AF: 0.00 AC: 0 AN: 35151

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19359

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841841

Other (OTH) AF: 0.0000217 AC: 1 AN: 46072

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.59
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.044
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.17
MutPred		0.25		Loss of phosphorylation at Y389 (P = 0.033)
MVP		0.26
MPC		0.12
ClinPred		0.56	D
GERP RS		2.1
gMVP		0.14
Mutation Taster		=90/10	polymorphism

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: rs372963755; hg19: chrX-101139233;