15-90360363-C-A

Variant names:

• chr15-90360363-C-A
• rs368002655
• NM_001004309.3:c.532C>A

Variant summary

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

The NM_001004309.3(ZNF774):​c.532C>A​(p.Pro178Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P178L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: ZNF774 NM_001004309.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.62
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.532C>A	p.Pro178Thr	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.532C>A	p.Pro178Thr	missense	Exon 4 of 4	ENSP00000346348.3	Q6NX45
	ZNF774	ENST00000379090.9	TSL:1	c.211+1406C>A		intron	N/A	ENSP00000368383.5	E7EQ77
	ZNF774	ENST00000558115.1	TSL:3	n.524C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251450 AF XY: 0.00000736

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461868 Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

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

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1112006

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.47
MPC		0.31
ClinPred		0.89	D
GERP RS		4.2
Varity_R		0.26
gMVP		0.10
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368002655; hg19: chr15-90903595;