19-20104344-T-A

Variant names:

• chr19-20104344-T-A
• rs782582504
• NM_007138.2:c.109T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007138.2(ZNF90):​c.109T>A​(p.Tyr37Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y37H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF90 NM_007138.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82
• Publications: 0 publications found

Genes affected

ZNF90 (HGNC:13165): (zinc finger protein 90) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF90	NM_007138.2	c.109T>A	p.Tyr37Asn	missense_variant	Exon 2 of 4	ENST00000418063.3	NP_009069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF90	ENST00000418063.3	c.109T>A	p.Tyr37Asn	missense_variant	Exon 2 of 4	1	NM_007138.2	ENSP00000410466.2
ZNF90	ENST00000469078.5	n.109T>A		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000420111.1
ZNF90	ENST00000473524.5	n.109T>A		non_coding_transcript_exon_variant	Exon 2 of 5	3		ENSP00000418166.1
ZNF90	ENST00000474284.1	n.143-877T>A		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461540 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727072

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111858

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74374

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

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.109T>A (p.Y37N) alteration is located in exon 2 (coding exon 2) of the ZNF90 gene. This alteration results from a T to A substitution at nucleotide position 109, causing the tyrosine (Y) at amino acid position 37 to be replaced by an asparagine (N). 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.048	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.0013	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		1.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Benign	0.078
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.38
MutPred		0.73		Loss of helix (P = 0.0237);
MVP		0.54
MPC		0.0041
ClinPred		0.99	D
GERP RS		1.1
Varity_R		0.069
gMVP		0.049
Mutation Taster		=86/14	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: rs782582504; hg19: chr19-20215153;