chrX-46500560-C-T

Variant names:

• chrX-46500560-C-T
• rs377291882
• NM_001190417.2:c.1014G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001190417.2(ZNF674):​c.1014G>A​(p.Thr338Thr) 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 (no stars).

• 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 no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0430
• Publications: 0 publications found

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]

ZNF674 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: Ambry Genetics
• X-linked intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 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 no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.043 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2	c.1014G>A	p.Thr338Thr	synonymous_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3	c.1029G>A	p.Thr343Thr	synonymous_variant	Exon 6 of 6		NP_001034980.1
ZNF674	NM_001146291.2	c.1011G>A	p.Thr337Thr	synonymous_variant	Exon 6 of 6		NP_001139763.1
ZNF674	XM_011543943.4	c.1026G>A	p.Thr342Thr	synonymous_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.1014G>A	p.Thr338Thr	synonymous_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1
ZNF674	ENST00000523374.5	c.1029G>A	p.Thr343Thr	synonymous_variant	Exon 6 of 6	1		ENSP00000429148.1
ZNF674	ENST00000414387.6	c.1011G>A	p.Thr337Thr	synonymous_variant	Exon 5 of 5	3		ENSP00000428248.1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112528 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.000127 AC: 23 AN: 181122 AF XY: 0.000209

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 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

African (AFR) AF: 0.0000379 AC: 1 AN: 26387

American (AMR) AF: 0.0000852 AC: 3 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30200

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54129

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.000264 AC: 222 AN: 841267

Other (OTH) AF: 0.000478 AC: 22 AN: 46051

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

African (AFR) AF: 0.000129 AC: 4 AN: 30973

American (AMR) AF: 0.000658 AC: 7 AN: 10633

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6133

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000206 AC: 11 AN: 53355

Other (OTH) AF: 0.00 AC: 0 AN: 1524

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: no assertion criteria provided

Submissions by phenotype

ZNF674-related disorder Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.043
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs377291882; hg19: chrX-46359995;