rs200552019

chrX-46500294-T-C

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.1280A>G(p.His427Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,209,606 control chromosomes in the GnomAD database, including 7 homozygotes. There are 232 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., 126 hem., cov: 23)
  • Exomes 𝑓: 0.00035 (3 hom. 106 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78

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=0.0057187676).
• BP6: Variant X-46500294-T-C is Benign according to our data. Variant chrX-46500294-T-C is described in ClinVar as [Benign]. Clinvar id is 130842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.1280A>G	p.His427Arg	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.1295A>G	p.His432Arg	missense_variant	6/6
ZNF674	NM_001146291.2	c.1277A>G	p.His426Arg	missense_variant	6/6
ZNF674	XM_011543943.4	c.1292A>G	p.His431Arg	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.1280A>G	p.His427Arg	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.1295A>G	p.His432Arg	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.1277A>G	p.His426Arg	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 424 AN: 112430 Hom.: 4 Cov.: 23 AF XY: 0.00356 AC XY: 123 AN XY: 34580

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000755

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000365

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00198

GnomAD3 exomes AF: 0.00104 AC: 189 AN: 181673 Hom.: 1 AF XY: 0.000743 AC XY: 50 AN XY: 67303

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000109

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: 0.0000247

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000347 AC: 381 AN: 1097122 Hom.: 3 Cov.: 30 AF XY: 0.000292 AC XY: 106 AN XY: 362520

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000250

Gnomad4 OTH exome AF: 0.000478

GnomAD4 genome AF: 0.00380 AC: 427 AN: 112484 Hom.: 4 Cov.: 23 AF XY: 0.00364 AC XY: 126 AN XY: 34644

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.000754

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000366

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000751

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.000507 Hom.: 19

Bravo AF: 0.00442

ESP6500AA AF: 0.0132 AC: 50

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00122 AC: 148

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 08, 2013

- -

ZNF674-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.88
Cadd	Benign	19
Dann	Benign	0.93
DEOGEN2	Benign	0.0047	T;.
FATHMM_MKL	Benign	0.00023	N
LIST_S2	Benign	0.30	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.041
Sift	Benign	0.031	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.052	B;.
Vest4		0.078
MVP		0.76
MPC		0.35
ClinPred		0.012	T
GERP RS		2.2
Varity_R		0.19
gMVP		0.094

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: rs200552019; hg19: chrX-46359729; COSMIC: COSV70379306; COSMIC: COSV70379306;