X-46500561-G-A

Variant names:

• chrX-46500561-G-A
• rs61730637
• NM_001190417.2:c.1013C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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:4
• 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2	c.1013C>T	p.Thr338Met	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3	c.1028C>T	p.Thr343Met	missense_variant	Exon 6 of 6		NP_001034980.1
ZNF674	NM_001146291.2	c.1010C>T	p.Thr337Met	missense_variant	Exon 6 of 6		NP_001139763.1
ZNF674	XM_011543943.4	c.1025C>T	p.Thr342Met	missense_variant	Exon 6 of 6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF674	ENST00000683375.1	c.1013C>T	p.Thr338Met	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1
ZNF674	ENST00000523374.5	c.1028C>T	p.Thr343Met	missense_variant	Exon 6 of 6	1		ENSP00000429148.1
ZNF674	ENST00000414387.6	c.1010C>T	p.Thr337Met	missense_variant	Exon 5 of 5	3		ENSP00000428248.1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 3319 AN: 112492 Hom.: 110 Cov.: 23

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

GnomAD2 exomes AF: 0.00838 AC: 1518 AN: 181144 AF XY: 0.00569

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 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

African (AFR) AF: 0.101 AC: 2659 AN: 26384

American (AMR) AF: 0.00648 AC: 228 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.000591 AC: 32 AN: 54119

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40473

Middle Eastern (MID) AF: 0.00750 AC: 31 AN: 4135

European-Non Finnish (NFE) AF: 0.000617 AC: 519 AN: 841174

Other (OTH) AF: 0.00810 AC: 373 AN: 46049

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

African (AFR) AF: 0.101 AC: 3121 AN: 30963

American (AMR) AF: 0.0135 AC: 144 AN: 10629

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00146 AC: 4 AN: 2731

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6176

Middle Eastern (MID) AF: 0.00926 AC: 2 AN: 216

European-Non Finnish (NFE) AF: 0.000937 AC: 50 AN: 53362

Other (OTH) AF: 0.0188 AC: 29 AN: 1543

Alfa AF: 0.0133 Hom.: 409

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 07, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

ZNF674-related disorder Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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;.
PhyloP100		-0.60
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
Mutation Taster		=100/0	polymorphism (auto)

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

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Other links and lift over

dbSNP: rs61730637; hg19: chrX-46359996;