13-32311544-G-T

Position:

• chr13-32311544-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136571.2(ZAR1L):​c.382C>A​(p.Pro128Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ZAR1L NM_001136571.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.18

Genes affected

ZAR1L (HGNC:37116): (zygote arrest 1 like) This gene encodes a member of the ZAR1 family that is predominantly expressed in oocytes and early embryos. The protein may function as an RNA regulator in early embryos. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04193166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZAR1L	NM_001136571.2	c.382C>A	p.Pro128Thr	missense_variant	3/6	ENST00000533490.7	NP_001130043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZAR1L	ENST00000533490.7	c.382C>A	p.Pro128Thr	missense_variant	3/6	5	NM_001136571.2	ENSP00000437289.2
ZAR1L	ENST00000345108.6	c.382C>A	p.Pro128Thr	missense_variant	1/4	1		ENSP00000344616.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 680432

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: 9.33e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

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

Sep 03, 2024

The c.382C>A (p.P128T) alteration is located in exon 1 (coding exon 1) of the ZAR1L gene. This alteration results from a C to A substitution at nucleotide position 382, causing the proline (P) at amino acid position 128 to be replaced by a threonine (T). 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	0.070
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.11
DANN	Benign	0.69
DEOGEN2	Benign	0.0046	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.31	.;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.23	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.0	.;N
REVEL	Benign	0.030
Sift	Benign	0.61	.;T
Sift4G	Benign	0.49	T;T
Polyphen		0.0020	B;B
Vest4		0.030
MutPred		0.20		Gain of catalytic residue at V132 (P = 0.0011);Gain of catalytic residue at V132 (P = 0.0011);
MVP		0.014
ClinPred		0.074	T
GERP RS		-4.8
Varity_R		0.034
gMVP		0.14

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: rs1268201629; hg19: chr13-32885681; COSMIC: COSV61526301; COSMIC: COSV61526301;