X-46500560-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001190417.2(ZNF674):c.1014G>A(p.Thr338=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,209,763 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 89 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00023 (0 hom. 85 hem.)
• Consequence: ZNF674 NM_001190417.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0430

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-46500560-C-T is Benign according to our data. Variant chrX-46500560-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3039339.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.043 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.1014G>A	p.Thr338=	synonymous_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.1029G>A	p.Thr343=	synonymous_variant	6/6
ZNF674	NM_001146291.2	c.1011G>A	p.Thr337=	synonymous_variant	6/6
ZNF674	XM_011543943.4	c.1026G>A	p.Thr342=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.1014G>A	p.Thr338=	synonymous_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.1029G>A	p.Thr343=	synonymous_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.1011G>A	p.Thr337=	synonymous_variant	5/5	3		A1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112528 Hom.: 0 Cov.: 23 AF XY: 0.000115 AC XY: 4 AN XY: 34692

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000658

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 23 AN: 181122 Hom.: 0 AF XY: 0.000209 AC XY: 14 AN XY: 67098

Gnomad AFR exome AF: 0.0000806

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000223

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000229 AC: 251 AN: 1097235 Hom.: 0 Cov.: 31 AF XY: 0.000234 AC XY: 85 AN XY: 362683

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.000478

GnomAD4 genome AF: 0.000196 AC: 22 AN: 112528 Hom.: 0 Cov.: 23 AF XY: 0.000115 AC XY: 4 AN XY: 34692

Gnomad4 AFR AF: 0.000129

Gnomad4 AMR AF: 0.000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000356 Hom.: 2

Bravo AF: 0.000336

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZNF674-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.94
Dann	Benign	0.48

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: rs377291882; hg19: chrX-46359995;