X-46500561-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001190417.2(ZNF674):c.1013C>T(p.Thr338Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,209,660 control chromosomes in the GnomAD database, including 212 homozygotes. There are 2,032 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T338T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.030 (112 hom., 955 hem., cov: 23)
  • Exomes 𝑓: 0.0035 (100 hom. 1077 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.596

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025901496).
• BP6: Variant X-46500561-G-A is Benign according to our data. Variant chrX-46500561-G-A is described in ClinVar as [Benign]. Clinvar id is 130843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.1013C>T	p.Thr338Met	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.1028C>T	p.Thr343Met	missense_variant	6/6
ZNF674	NM_001146291.2	c.1010C>T	p.Thr337Met	missense_variant	6/6
ZNF674	XM_011543943.4	c.1025C>T	p.Thr342Met	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.1013C>T	p.Thr338Met	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.1028C>T	p.Thr343Met	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.1010C>T	p.Thr337Met	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 3319 AN: 112492 Hom.: 110 Cov.: 23 AF XY: 0.0270 AC XY: 935 AN XY: 34662

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000937

Gnomad OTH AF: 0.0190

GnomAD3 exomes AF: 0.00838 AC: 1518 AN: 181144 Hom.: 44 AF XY: 0.00569 AC XY: 382 AN XY: 67100

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00351 AC: 3846 AN: 1097117 Hom.: 100 Cov.: 31 AF XY: 0.00297 AC XY: 1077 AN XY: 362593

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00648

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.000617

Gnomad4 OTH exome AF: 0.00810

GnomAD4 genome AF: 0.0298 AC: 3350 AN: 112543 Hom.: 112 Cov.: 23 AF XY: 0.0275 AC XY: 955 AN XY: 34723

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000937

Gnomad4 OTH AF: 0.0188

Alfa AF: 0.00472 Hom.: 101

Bravo AF: 0.0332

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.0919 AC: 300

ESP6500EA AF: 0.000618 AC: 4

ExAC AF: 0.00913 AC: 1104

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2017	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. -

ZNF674-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 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	0.15
BayesDel_addAF	Benign	-0.94	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.55
Dann	Benign	0.52
DEOGEN2	Benign	0.0061	T;.
FATHMM_MKL	Benign	0.000050	N
LIST_S2	Benign	0.095	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.27
Sift	Benign	0.037	D;T
Sift4G	Uncertain	0.015	D;D
Polyphen		0.99	D;.
Vest4		0.058
MVP		0.38
MPC		0.35
ClinPred		0.015	T
GERP RS		-4.9
Varity_R		0.016
gMVP		0.050

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: rs61730637; hg19: chrX-46359996;