chr7-149475100-T-G

Variant names:

• chr7-149475100-T-G
• rs958084329
• NM_001394198.1:c.1267A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001394198.1(ZNF746):​c.1267A>C​(p.Asn423His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,607,970 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZNF746 NM_001394198.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.102
• Publications: 0 publications found

Genes affected

ZNF746 (HGNC:21948): (zinc finger protein 746) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and ubiquitin protein ligase binding activity. Involved in negative regulation of transcription by RNA polymerase II; positive regulation of neuron death; and positive regulation of transcription by RNA polymerase II. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05019608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF746	NM_001394198.1	c.1267A>C	p.Asn423His	missense_variant	Exon 7 of 7	ENST00000458143.7	NP_001381127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF746	ENST00000458143.7	c.1267A>C	p.Asn423His	missense_variant	Exon 7 of 7	2	NM_001394198.1	ENSP00000395007.3
ZNF746	ENST00000340622.8	c.1219A>C	p.Asn407His	missense_variant	Exon 7 of 7	1		ENSP00000345140.3
ZNF746	ENST00000644635.1	c.1264A>C	p.Asn422His	missense_variant	Exon 7 of 7			ENSP00000493970.1
ZNF746	ENST00000685153.1	c.1222A>C	p.Asn408His	missense_variant	Exon 7 of 7			ENSP00000508891.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000127 AC: 3 AN: 236740 AF XY: 0.00000774

Gnomad AFR exome AF: 0.000208

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1455870 Hom.: 0 Cov.: 31 AF XY: 0.00000691 AC XY: 5 AN XY: 723838

African (AFR) AF: 0.000180 AC: 6 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 43792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 85408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110112

Other (OTH) AF: 0.00 AC: 0 AN: 60108

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1222A>C (p.N408H) alteration is located in exon 7 (coding exon 7) of the ZNF746 gene. This alteration results from a A to C substitution at nucleotide position 1222, causing the asparagine (N) at amino acid position 408 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.62
DEOGEN2	Benign	0.011	.;T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	.;N;.
PhyloP100		-0.10
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.27	.;N;N
REVEL	Benign	0.083
Sift	Benign	0.56	.;T;T
Sift4G	Benign	0.17	.;T;T
Polyphen		0.0	.;B;B
Vest4		0.10, 0.10
MutPred		0.45		.;Gain of catalytic residue at E409 (P = 0.1013);.;
MVP		0.30
MPC		0.77
ClinPred		0.0090	T
GERP RS		1.8
Varity_R		0.081
gMVP		0.17
Mutation Taster		=99/1	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: rs958084329; hg19: chr7-149172191;