19-44172109-G-A

Variant names:

• chr19-44172109-G-A
• rs752607335
• NM_001032373.2:c.37G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001032373.2(ZNF226):​c.37G>A​(p.Val13Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ZNF226 NM_001032373.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72
• Publications: 1 publications found

Genes affected

ZNF226 (HGNC:13019): (zinc finger protein 226) Predicted to enable DNA-binding transcription activator 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 by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF226	NM_001032373.2	c.37G>A	p.Val13Met	missense_variant	Exon 4 of 6	ENST00000337433.10	NP_001027545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF226	ENST00000337433.10	c.37G>A	p.Val13Met	missense_variant	Exon 4 of 6	1	NM_001032373.2	ENSP00000336719.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251412 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460212 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726414

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110934

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.37G>A (p.V13M) alteration is located in exon 4 (coding exon 2) of the ZNF226 gene. This alteration results from a G to A substitution at nucleotide position 37, causing the valine (V) at amino acid position 13 to be replaced by a methionine (M). 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	Pathogenic	0.60
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;.;T;.;.;.;.;.;.;.;.;.;.;.;T;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;T;.;.;.;D;D;D;D;D;.;.;D
M_CAP	Benign	0.0070	T
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	.;.;M;.;.;.;.;M;M;M;.;.;.;.;M;M;.
PhyloP100		2.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	.;.;D;.;.;.;.;D;.;D;.;.;.;.;.;D;.
REVEL	Benign	0.18
Sift	Pathogenic	0.0	.;.;D;.;.;.;.;D;.;D;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.96	.;.;D;.;.;.;.;.;.;.;.;.;.;.;D;D;.
Vest4		0.39, 0.32, 0.38, 0.41, 0.33
MutPred		0.80		Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);Gain of phosphorylation at T18 (P = 0.0853);
MVP		0.40
MPC		0.15
ClinPred		0.86	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.22
Mutation Taster		=91/9	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: rs752607335; hg19: chr19-44676262; COSMIC: COSV100334989;