X-46500034-G-T

Variant names:

• chrX-46500034-G-T
• rs955437777
• NM_001190417.2:c.1540C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001190417.2(ZNF674):​c.1540C>A​(p.His514Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,388 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1540C>A	p.His514Asn	missense	Exon 6 of 6	NP_001177346.1	A0A804HHU7
	ZNF674	NM_001039891.3		c.1555C>A	p.His519Asn	missense	Exon 6 of 6	NP_001034980.1	Q2M3X9-1
	ZNF674	NM_001146291.2		c.1537C>A	p.His513Asn	missense	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.1540C>A	p.His514Asn	missense	Exon 6 of 6	ENSP00000506769.1	A0A804HHU7
	ZNF674	ENST00000523374.5	TSL:1	c.1555C>A	p.His519Asn	missense	Exon 6 of 6	ENSP00000429148.1	Q2M3X9-1
	ZNF674	ENST00000878263.1		c.1540C>A	p.His514Asn	missense	Exon 6 of 6	ENSP00000548322.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097388 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362808

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.0000285 AC: 1 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30167

South Asian (SAS) AF: 0.00 AC: 0 AN: 54052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841679

Other (OTH) AF: 0.00 AC: 0 AN: 46062

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.75		Loss of catalytic residue at R517 (P = 0.0691)
MVP		0.77
MPC		0.85
ClinPred		0.99	D
GERP RS		1.4
Varity_R		0.77
gMVP		0.12
Mutation Taster		=79/21	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: rs955437777; hg19: chrX-46359469;