19-34958086-A-C

Variant names:

• chr19-34958086-A-C
• rs758946455
• NM_175872.5:c.1769T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_175872.5(ZNF792):​c.1769T>G​(p.Met590Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,612,558 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. M590V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (3 hom.)
• Consequence: ZNF792 NM_175872.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.937
• Publications: 1 publications found

Genes affected

ZNF792 (HGNC:24751): (zinc finger protein 792) Enables identical protein 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05755782).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF792	NM_175872.5	c.1769T>G	p.Met590Arg	missense_variant	Exon 4 of 4	ENST00000404801.2	NP_787068.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF792	ENST00000404801.2	c.1769T>G	p.Met590Arg	missense_variant	Exon 4 of 4	2	NM_175872.5	ENSP00000385099.1
ZNF792	ENST00000605484.1	c.1568T>G	p.Met523Arg	missense_variant	Exon 2 of 2	1		ENSP00000474130.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000443 AC: 11 AN: 248266 AF XY: 0.0000373

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000494

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1460402 Hom.: 3 Cov.: 32 AF XY: 0.000143 AC XY: 104 AN XY: 726332

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00532 AC: 211 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111288

Other (OTH) AF: 0.0000497 AC: 3 AN: 60324

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1769T>G (p.M590R) alteration is located in exon 4 (coding exon 4) of the ZNF792 gene. This alteration results from a T to G substitution at nucleotide position 1769, causing the methionine (M) at amino acid position 590 to be replaced by an arginine (R). 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	0.081
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.1
DANN	Benign	0.75
DEOGEN2	Benign	0.0033	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00077	N
LIST_S2	Benign	0.050	T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		-0.94
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.67	N;.
REVEL	Benign	0.027
Sift	Benign	0.035	D;.
Sift4G	Uncertain	0.044	D;D
Polyphen		0.0090	B;.
Vest4		0.19
MutPred		0.65		Gain of disorder (P = 0.0227);.;
MVP		0.14
MPC		0.24
ClinPred		0.0080	T
GERP RS		-2.4
Varity_R		0.23
gMVP		0.15
Mutation Taster		=93/7	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: rs758946455; hg19: chr19-35448990; COSMIC: COSV68693015;