chr19-23359698-G-C

Position:

• chr19-23359698-G-C

Variant summary

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

The NM_003430.4(ZNF91):​c.3281C>G​(p.Thr1094Ser) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF91 NM_003430.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.26

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 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=0.0554125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF91	NM_003430.4	c.3281C>G	p.Thr1094Ser	missense_variant	4/4	ENST00000300619.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF91	ENST00000300619.12	c.3281C>G	p.Thr1094Ser	missense_variant	4/4	1	NM_003430.4	P1
ZNF91	ENST00000397082.2	c.3185C>G	p.Thr1062Ser	missense_variant	3/3	2
ZNF91	ENST00000599743.5	c.253+14044C>G		intron_variant		3
ZNF91	ENST00000596989.1	n.370+14044C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Aug 11, 2022

The c.3281C>G (p.T1094S) alteration is located in exon 4 (coding exon 4) of the ZNF91 gene. This alteration results from a C to G substitution at nucleotide position 3281, causing the threonine (T) at amino acid position 1094 to be replaced by a serine (S). 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	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.0
DANN	Benign	0.54
DEOGEN2	Benign	0.0038	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.17	T;T
M_CAP	Benign	0.00090	T
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.056
Sift	Benign	0.58	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.89	P;P
Vest4		0.031
MutPred		0.28		Gain of catalytic residue at T1094 (P = 0.0399);.;
MVP		0.23
MPC		0.35
ClinPred		0.12	T
GERP RS		-1.1
Varity_R		0.031
gMVP		0.0048

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: rs1968636945; hg19: chr19-23542500;