X-46500690-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001190417.2(ZNF674):c.884G>A(p.Arg295Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000825 in 1,210,281 control chromosomes in the GnomAD database, including 8 homozygotes. There are 257 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., 133 hem., cov: 22)
  • Exomes 𝑓: 0.00046 (5 hom. 124 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.44

Genes affected

ZNF674 (HGNC:17625): (zinc finger protein 674) This gene encodes a zinc finger protein with an N-terminal Kruppel-associated box-containing (KRAB) domain and 11 Kruppel-type C2H2 zinc finger domains. Like other zinc finger proteins, this gene may function as a transcription factor. This gene resides on an area of chromosome X that has been implicated in nonsyndromic X-linked cognitive disabilities. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052367747).
• BP6: Variant X-46500690-C-T is Benign according to our data. Variant chrX-46500690-C-T is described in ClinVar as [Benign]. Clinvar id is 93485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-46500690-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.884G>A	p.Arg295Gln	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.899G>A	p.Arg300Gln	missense_variant	6/6
ZNF674	NM_001146291.2	c.881G>A	p.Arg294Gln	missense_variant	6/6
ZNF674	XM_011543943.4	c.896G>A	p.Arg299Gln	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.884G>A	p.Arg295Gln	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.899G>A	p.Arg300Gln	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.881G>A	p.Arg294Gln	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 496 AN: 112189 Hom.: 3 Cov.: 22 AF XY: 0.00384 AC XY: 132 AN XY: 34363

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.0000188

Gnomad OTH AF: 0.00198

GnomAD3 exomes AF: 0.00109 AC: 198 AN: 181642 Hom.: 1 AF XY: 0.000848 AC XY: 57 AN XY: 67206

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.000476

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000898

GnomAD4 exome AF: 0.000456 AC: 501 AN: 1098038 Hom.: 5 Cov.: 31 AF XY: 0.000341 AC XY: 124 AN XY: 363434

Gnomad4 AFR exome AF: 0.0153

Gnomad4 AMR exome AF: 0.000711

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000392

Gnomad4 OTH exome AF: 0.000803

GnomAD4 genome AF: 0.00444 AC: 498 AN: 112243 Hom.: 3 Cov.: 22 AF XY: 0.00386 AC XY: 133 AN XY: 34427

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.000456 Hom.: 19

Bravo AF: 0.00544

ESP6500AA AF: 0.0114 AC: 43

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00128 AC: 155

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 16, 2015	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2013	- -

ZNF674-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.047	T;.
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.30	T;T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.055
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;.
Vest4		0.27
MVP		0.49
MPC		0.26
ClinPred		0.028	T
GERP RS		0.19
Varity_R		0.16
gMVP		0.027

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

LitVar

Other links and lift over

dbSNP: rs187237351; hg19: chrX-46360125;