rs182004761

Variant names:

• chrX-46500988-G-A
• rs182004761
• NM_001190417.2:c.586C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001190417.2(ZNF674):​c.586C>T​(p.Arg196*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,192,467 control chromosomes in the GnomAD database, including 16 homozygotes. There are 2,387 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (0 hom., 91 hem., cov: 22)
  • Exomes 𝑓: 0.0065 (16 hom. 2296 hem.)
• Consequence: ZNF674 NM_001190417.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.832
• Publications: 6 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant X-46500988-G-A is Benign according to our data. Variant chrX-46500988-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130846.
• BS2: High Hemizygotes in GnomAd4 at 91 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	NM_001190417.2	MANE Select	c.586C>T	p.Arg196*	stop_gained	Exon 6 of 6	NP_001177346.1	A0A804HHU7
	ZNF674	NM_001039891.3		c.601C>T	p.Arg201*	stop_gained	Exon 6 of 6	NP_001034980.1	Q2M3X9-1
	ZNF674	NM_001146291.2		c.583C>T	p.Arg195*	stop_gained	Exon 6 of 6	NP_001139763.1	Q2M3X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	ENST00000683375.1	MANE Select	c.586C>T	p.Arg196*	stop_gained	Exon 6 of 6	ENSP00000506769.1	A0A804HHU7
	ZNF674	ENST00000523374.5	TSL:1	c.601C>T	p.Arg201*	stop_gained	Exon 6 of 6	ENSP00000429148.1	Q2M3X9-1
	ZNF674	ENST00000878263.1		c.586C>T	p.Arg196*	stop_gained	Exon 6 of 6	ENSP00000548322.1

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 412 AN: 110253 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00166

Gnomad ASJ AF: 0.00607

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00347

Gnomad FIN AF: 0.00139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00618

Gnomad OTH AF: 0.00203

GnomAD2 exomes AF: 0.00380 AC: 587 AN: 154330 AF XY: 0.00438

Gnomad AFR exome AF: 0.000643

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00600

Gnomad EAS exome AF: 0.0000843

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00650

Gnomad OTH exome AF: 0.00404

GnomAD4 exome AF: 0.00652 AC: 7056 AN: 1082161 Hom.: 16 Cov.: 31 AF XY: 0.00651 AC XY: 2296 AN XY: 352951

African (AFR) AF: 0.00122 AC: 32 AN: 26228

American (AMR) AF: 0.00152 AC: 49 AN: 32289

Ashkenazi Jewish (ASJ) AF: 0.00535 AC: 102 AN: 19064

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29799

South Asian (SAS) AF: 0.00203 AC: 106 AN: 52250

European-Finnish (FIN) AF: 0.00212 AC: 84 AN: 39640

Middle Eastern (MID) AF: 0.00146 AC: 6 AN: 4101

European-Non Finnish (NFE) AF: 0.00774 AC: 6446 AN: 833296

Other (OTH) AF: 0.00506 AC: 230 AN: 45494

GnomAD4 genome AF: 0.00374 AC: 412 AN: 110306 Hom.: 0 Cov.: 22 AF XY: 0.00279 AC XY: 91 AN XY: 32570

African (AFR) AF: 0.00109 AC: 33 AN: 30366

American (AMR) AF: 0.00165 AC: 17 AN: 10278

Ashkenazi Jewish (ASJ) AF: 0.00607 AC: 16 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3535

South Asian (SAS) AF: 0.00348 AC: 9 AN: 2583

European-Finnish (FIN) AF: 0.00139 AC: 8 AN: 5766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00618 AC: 326 AN: 52744

Other (OTH) AF: 0.00200 AC: 3 AN: 1500

Alfa AF: 0.00518 Hom.: 51

Bravo AF: 0.00361

ESP6500AA AF: 0.00159 AC: 5

ESP6500EA AF: 0.00612 AC: 39

ExAC AF: 0.00410 AC: 492

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	2	not specified (2)
-	-	1	ZNF674-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.023	N
PhyloP100		0.83
Vest4		0.078
GERP RS		0.93
Mutation Taster		=194/6	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: rs182004761; hg19: chrX-46360423;