19-23360338-G-A

Position:

• chr19-23360338-G-A

Variant summary

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

The NM_003430.4(ZNF91):​c.2641C>T​(p.Pro881Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF91 NM_003430.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15487275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF91	NM_003430.4	c.2641C>T	p.Pro881Ser	missense_variant	4/4	ENST00000300619.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF91	ENST00000300619.12	c.2641C>T	p.Pro881Ser	missense_variant	4/4	1	NM_003430.4	P1
ZNF91	ENST00000397082.2	c.2545C>T	p.Pro849Ser	missense_variant	3/3	2
ZNF91	ENST00000599743.5	c.253+13404C>T		intron_variant		3
ZNF91	ENST00000596989.1	n.370+13404C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461782 Hom.: 0 Cov.: 80 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000896

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000252 Hom.: 0

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 22, 2022

The c.2641C>T (p.P881S) alteration is located in exon 4 (coding exon 4) of the ZNF91 gene. This alteration results from a C to T substitution at nucleotide position 2641, causing the proline (P) at amino acid position 881 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	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.069	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Benign	0.099
Sift	Benign	0.032	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.77	P;P
Vest4		0.12
MVP		0.29
MPC		0.48
ClinPred		0.36	T
GERP RS		0.066
Varity_R		0.10
gMVP		0.0094

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: rs755914444; hg19: chr19-23543140;