X-46500464-A-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.1110T>G(p.His370Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000681 in 1,210,453 control chromosomes in the GnomAD database, including 7 homozygotes. There are 243 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., 132 hem., cov: 23)
  • Exomes 𝑓: 0.00036 (3 hom. 111 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.831

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=0.007127017).
• BP6: Variant X-46500464-A-C is Benign according to our data. Variant chrX-46500464-A-C is described in ClinVar as [Benign]. Clinvar id is 130841.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.1110T>G	p.His370Gln	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.1125T>G	p.His375Gln	missense_variant	6/6
ZNF674	NM_001146291.2	c.1107T>G	p.His369Gln	missense_variant	6/6
ZNF674	XM_011543943.4	c.1122T>G	p.His374Gln	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.1110T>G	p.His370Gln	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.1125T>G	p.His375Gln	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.1107T>G	p.His369Gln	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 430 AN: 112422 Hom.: 4 Cov.: 23 AF XY: 0.00370 AC XY: 128 AN XY: 34606

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000362

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000750

Gnomad OTH AF: 0.00197

GnomAD3 exomes AF: 0.00105 AC: 190 AN: 181443 Hom.: 1 AF XY: 0.000773 AC XY: 52 AN XY: 67303

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000146

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: 0.000675

GnomAD4 exome AF: 0.000355 AC: 390 AN: 1097977 Hom.: 3 Cov.: 31 AF XY: 0.000305 AC XY: 111 AN XY: 363411

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000249

Gnomad4 OTH exome AF: 0.000608

GnomAD4 genome AF: 0.00386 AC: 434 AN: 112476 Hom.: 4 Cov.: 23 AF XY: 0.00381 AC XY: 132 AN XY: 34670

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000363

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000750

Gnomad4 OTH AF: 0.00195

Alfa AF: 0.000256 Hom.: 9

Bravo AF: 0.00444

ESP6500AA AF: 0.0128 AC: 44

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00120 AC: 145

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 disorder 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	0.34
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	16
Dann	Benign	0.73
DEOGEN2	Benign	0.16	T;.
FATHMM_MKL	Benign	0.00075	N
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0071	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.91	P;.
Vest4		0.21
MutPred		0.48		Loss of glycosylation at T373 (P = 0.0692);.;
MVP		0.87
MPC		0.21
ClinPred		0.064	T
GERP RS		-1.9
Varity_R		0.30
gMVP		0.052

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: rs142411452; hg19: chrX-46359899; COSMIC: COSV70379309; COSMIC: COSV70379309;