rs200552019

Variant names:

• chrX-46500294-T-C
• rs200552019
• NM_001190417.2:c.1280A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001190417.2(ZNF674):​c.1280A>G​(p.His427Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,209,606 control chromosomes in the GnomAD database, including 7 homozygotes. There are 232 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., 126 hem., cov: 23)
  • Exomes 𝑓: 0.00035 (3 hom. 106 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.78
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057187676).
• BP6: Variant X-46500294-T-C is Benign according to our data. Variant chrX-46500294-T-C is described in ClinVar as Benign. ClinVar VariationId is 130842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190417.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	NM_001190417.2	MANE Select	c.1280A>G	p.His427Arg	missense	Exon 6 of 6	NP_001177346.1
	ZNF674	NM_001039891.3		c.1295A>G	p.His432Arg	missense	Exon 6 of 6	NP_001034980.1
	ZNF674	NM_001146291.2		c.1277A>G	p.His426Arg	missense	Exon 6 of 6	NP_001139763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	ENST00000683375.1	MANE Select	c.1280A>G	p.His427Arg	missense	Exon 6 of 6	ENSP00000506769.1
	ZNF674	ENST00000523374.5	TSL:1	c.1295A>G	p.His432Arg	missense	Exon 6 of 6	ENSP00000429148.1
	ZNF674	ENST00000414387.6	TSL:3	c.1277A>G	p.His426Arg	missense	Exon 5 of 5	ENSP00000428248.1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 424 AN: 112430 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000755

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000365

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00198

GnomAD2 exomes AF: 0.00104 AC: 189 AN: 181673 AF XY: 0.000743

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000347 AC: 381 AN: 1097122 Hom.: 3 Cov.: 30 AF XY: 0.000292 AC XY: 106 AN XY: 362520

African (AFR) AF: 0.0123 AC: 324 AN: 26379

American (AMR) AF: 0.000256 AC: 9 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54125

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40466

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4135

European-Non Finnish (NFE) AF: 0.0000250 AC: 21 AN: 841194

Other (OTH) AF: 0.000478 AC: 22 AN: 46046

GnomAD4 genome AF: 0.00380 AC: 427 AN: 112484 Hom.: 4 Cov.: 23 AF XY: 0.00364 AC XY: 126 AN XY: 34644

African (AFR) AF: 0.0133 AC: 411 AN: 31008

American (AMR) AF: 0.000754 AC: 8 AN: 10616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.000366 AC: 1 AN: 2731

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53279

Other (OTH) AF: 0.00196 AC: 3 AN: 1533

Alfa AF: 0.00147 Hom.: 61

Bravo AF: 0.00442

ESP6500AA AF: 0.0132 AC: 50

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00122 AC: 148

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	ZNF674-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.0047	T
FATHMM_MKL	Benign	0.00023	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.041
Sift	Benign	0.031	D
Sift4G	Benign	0.14	T
Polyphen		0.052	B
Vest4		0.078
MVP		0.76
MPC		0.35
ClinPred		0.012	T
GERP RS		2.2
Varity_R		0.19
gMVP		0.094
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs200552019; hg19: chrX-46359729; COSMIC: COSV70379306; COSMIC: COSV70379306;