chr7-149474473-A-C

Position:

• chr7-149474473-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001394198.1(ZNF746):​c.1894T>G​(p.Ser632Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF746 NM_001394198.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.58

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04408601).
• BP6: Variant 7-149474473-A-C is Benign according to our data. Variant chr7-149474473-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2555311.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF746	NM_001394198.1	c.1894T>G	p.Ser632Ala	missense_variant	7/7	ENST00000458143.7	NP_001381127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF746	ENST00000458143.7	c.1894T>G	p.Ser632Ala	missense_variant	7/7	2	NM_001394198.1	ENSP00000395007	A2
ZNF746	ENST00000340622.8	c.1846T>G	p.Ser616Ala	missense_variant	7/7	1		ENSP00000345140	P4
ZNF746	ENST00000644635.1	c.1891T>G	p.Ser631Ala	missense_variant	7/7			ENSP00000493970	A2
ZNF746	ENST00000685153.1	c.1849T>G	p.Ser617Ala	missense_variant	7/7			ENSP00000508891	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.11
DANN	Benign	0.54
DEOGEN2	Benign	0.017	.;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.31	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	.;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.34	.;N;N
REVEL	Benign	0.042
Sift	Benign	1.0	.;T;T
Sift4G	Benign	1.0	.;T;T
Polyphen		0.0	.;B;B
Vest4		0.067, 0.066
MutPred		0.29		.;Loss of glycosylation at S616 (P = 0.0048);.;
MVP		0.17
MPC		0.49
ClinPred		0.043	T
GERP RS		-11
Varity_R		0.048
gMVP		0.36

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-149171564;