chr19-23360244-C-T

Position:

• chr19-23360244-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003430.4(ZNF91):​c.2735G>A​(p.Cys912Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ZNF91 NM_003430.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

Genes affected

ZNF91 (HGNC:13166): (zinc finger protein 91) The ZNF91 gene encodes a zinc finger protein of the KRAB (Kruppel-associated box) subfamily (Bellefroid et al., 1991, 1993 [PubMed 2023909] [PubMed 8467795]).[supplied by OMIM, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF91	NM_003430.4	c.2735G>A	p.Cys912Tyr	missense_variant	4/4	ENST00000300619.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF91	ENST00000300619.12	c.2735G>A	p.Cys912Tyr	missense_variant	4/4	1	NM_003430.4	P1
ZNF91	ENST00000397082.2	c.2639G>A	p.Cys880Tyr	missense_variant	3/3	2
ZNF91	ENST00000599743.5	c.253+13498G>A		intron_variant		3
ZNF91	ENST00000596989.1	n.370+13498G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 34

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

Oct 25, 2022

The c.2735G>A (p.C912Y) alteration is located in exon 4 (coding exon 4) of the ZNF91 gene. This alteration results from a G to A substitution at nucleotide position 2735, causing the cysteine (C) at amino acid position 912 to be replaced by a tyrosine (Y). 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	0.27
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.74
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.17	T;T
M_CAP	Benign	0.0028	T
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.25
MutPred		0.91		Gain of phosphorylation at C912 (P = 0.0711);.;
MVP		0.75
MPC		1.0
ClinPred		0.83	D
GERP RS		0.13
Varity_R		0.65
gMVP		0.14

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: rs1045374145; hg19: chr19-23543046;