8-40697397-C-A

Variant summary

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

The NM_024645.3(ZMAT4):c.197G>T(p.Ser66Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,429,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ZMAT4 NM_024645.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.440

Genes affected

ZMAT4 (HGNC:25844): (zinc finger matrin-type 4) Enables identical protein binding activity. Predicted to be located in nucleus. [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=0.12875527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMAT4	NM_024645.3	c.197G>T	p.Ser66Ile	missense_variant	4/7	ENST00000297737.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMAT4	ENST00000297737.11	c.197G>T	p.Ser66Ile	missense_variant	4/7	2	NM_024645.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000851 AC: 2 AN: 235034 Hom.: 0 AF XY: 0.00000787 AC XY: 1 AN XY: 127064

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000327

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: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1429340 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 709032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000488

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: 0.00000274

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.197G>T (p.S66I) alteration is located in exon 4 (coding exon 3) of the ZMAT4 gene. This alteration results from a G to T substitution at nucleotide position 197, causing the serine (S) at amino acid position 66 to be replaced by an isoleucine (I). 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	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	10
Dann	Uncertain	0.99
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.90	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.034
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.015	D;D;.
Polyphen		0.28	B;P;.
Vest4		0.22
MutPred		0.28		Loss of disorder (P = 0.0047);Loss of disorder (P = 0.0047);Loss of disorder (P = 0.0047);
MVP		0.20
MPC		1.1
ClinPred		0.15	T
GERP RS		2.3
Varity_R		0.10
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs1260273781; hg19: chr8-40554916;