15-90360079-A-G

Variant names:

• chr15-90360079-A-G
• rs2589957
• NM_001004309.3:c.248A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001004309.3(ZNF774):​c.248A>G​(p.Asn83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,613,200 control chromosomes in the GnomAD database, including 216,243 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.58 (26837 hom., cov: 32)
  • Exomes 𝑓: 0.50 (189406 hom.)
• Consequence: ZNF774 NM_001004309.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219
• Publications: 42 publications found

Genes affected

ZNF774 (HGNC:33108): (zinc finger protein 774) 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 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.990085E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004309.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF774	NM_001004309.3	MANE Select	c.248A>G	p.Asn83Ser	missense	Exon 4 of 4	NP_001004309.2	Q6NX45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF774	ENST00000354377.8	TSL:1 MANE Select	c.248A>G	p.Asn83Ser	missense	Exon 4 of 4	ENSP00000346348.3	Q6NX45
	ZNF774	ENST00000379090.9	TSL:1	c.211+1122A>G		intron	N/A	ENSP00000368383.5	E7EQ77
	ZNF774	ENST00000558115.1	TSL:3	n.240A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87720 AN: 151940 Hom.: 26796 Cov.: 32

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.557

GnomAD2 exomes AF: 0.562 AC: 141104 AN: 250992 AF XY: 0.552

Gnomad AFR exome AF: 0.750

Gnomad AMR exome AF: 0.694

Gnomad ASJ exome AF: 0.435

Gnomad EAS exome AF: 0.858

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.526

GnomAD4 exome AF: 0.502 AC: 733088 AN: 1461142 Hom.: 189406 Cov.: 42 AF XY: 0.502 AC XY: 365155 AN XY: 726840

African (AFR) AF: 0.756 AC: 25278 AN: 33458

American (AMR) AF: 0.687 AC: 30699 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 11480 AN: 26102

East Asian (EAS) AF: 0.845 AC: 33549 AN: 39696

South Asian (SAS) AF: 0.592 AC: 51090 AN: 86228

European-Finnish (FIN) AF: 0.455 AC: 24292 AN: 53404

Middle Eastern (MID) AF: 0.480 AC: 2768 AN: 5764

European-Non Finnish (NFE) AF: 0.470 AC: 522594 AN: 1111436

Other (OTH) AF: 0.519 AC: 31338 AN: 60366

GnomAD4 genome AF: 0.578 AC: 87816 AN: 152058 Hom.: 26837 Cov.: 32 AF XY: 0.577 AC XY: 42887 AN XY: 74312

African (AFR) AF: 0.753 AC: 31213 AN: 41470

American (AMR) AF: 0.612 AC: 9350 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3472

East Asian (EAS) AF: 0.847 AC: 4387 AN: 5180

South Asian (SAS) AF: 0.587 AC: 2831 AN: 4826

European-Finnish (FIN) AF: 0.447 AC: 4714 AN: 10546

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 31989 AN: 67972

Other (OTH) AF: 0.556 AC: 1175 AN: 2112

Alfa AF: 0.518 Hom.: 54462

Bravo AF: 0.602

TwinsUK AF: 0.456 AC: 1692

ALSPAC AF: 0.483 AC: 1863

ESP6500AA AF: 0.746 AC: 3280

ESP6500EA AF: 0.475 AC: 4079

ExAC AF: 0.560 AC: 68048

Asia WGS AF: 0.692 AC: 2408 AN: 3478

EpiCase AF: 0.471

EpiControl AF: 0.475

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.60
DEOGEN2	Benign	0.00013	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.22
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.017
Sift	Benign	0.60	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.036
ClinPred		0.0041	T
GERP RS		1.7
Varity_R		0.032
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2589957; hg19: chr15-90903311; COSMIC: COSV107448941; COSMIC: COSV107448941;