rs440638

Variant names:

• chr19-23361616-A-T
• rs440638
• NM_003430.4:c.1363T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003430.4(ZNF91):​c.1363T>A​(p.Phe455Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 144,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF91 NM_003430.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 6 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021535397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF91	NM_003430.4	c.1363T>A	p.Phe455Ile	missense_variant	Exon 4 of 4	ENST00000300619.12	NP_003421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF91	ENST00000300619.12	c.1363T>A	p.Phe455Ile	missense_variant	Exon 4 of 4	1	NM_003430.4	ENSP00000300619.6
ZNF91	ENST00000397082.2	c.1267T>A	p.Phe423Ile	missense_variant	Exon 3 of 3	2		ENSP00000380272.2
ZNF91	ENST00000599743.5	c.253+12126T>A		intron_variant	Intron 3 of 3	3		ENSP00000468867.1
ZNF91	ENST00000596989.1	n.370+12126T>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000166 AC: 24 AN: 144568 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000214

Gnomad SAS AF: 0.000444

Gnomad FIN AF: 0.0000989

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000214

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000682 AC: 17 AN: 249308 AF XY: 0.0000592

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.000165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000958 AC: 140 AN: 1461292 Hom.: 1 Cov.: 62 AF XY: 0.0000922 AC XY: 67 AN XY: 726952

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000598 AC: 2 AN: 33460

American (AMR) AF: 0.0000671 AC: 3 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1111626

Other (OTH) AF: 0.000116 AC: 7 AN: 60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000166 AC: 24 AN: 144708 Hom.: 0 Cov.: 32 AF XY: 0.000170 AC XY: 12 AN XY: 70636

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000257 AC: 1 AN: 38930

American (AMR) AF: 0.000342 AC: 5 AN: 14640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3370

East Asian (EAS) AF: 0.000215 AC: 1 AN: 4654

South Asian (SAS) AF: 0.000444 AC: 2 AN: 4508

European-Finnish (FIN) AF: 0.0000989 AC: 1 AN: 10110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.000214 AC: 14 AN: 65442

Other (OTH) AF: 0.00 AC: 0 AN: 1990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000244205), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000288 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000116 AC: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.073
DANN	Benign	0.16
DEOGEN2	Benign	0.00049	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.022	T;T
M_CAP	Benign	0.00093	T
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;.
PhyloP100		-1.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	3.4	N;N
REVEL	Benign	0.0080
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.10
MVP		0.081
MPC		0.28
ClinPred		0.022	T
GERP RS		-3.4
Varity_R		0.027
gMVP		0.014
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs440638; hg19: chr19-23544418; COSMIC: COSV56080046; COSMIC: COSV56080046;