X-46500034-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.1540C>A	p.His514Asn	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.1555C>A	p.His519Asn	missense_variant	6/6
ZNF674	NM_001146291.2	c.1537C>A	p.His513Asn	missense_variant	6/6
ZNF674	XM_011543943.4	c.1552C>A	p.His518Asn	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.1540C>A	p.His514Asn	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.1555C>A	p.His519Asn	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.1537C>A	p.His513Asn	missense_variant	5/5	3		A1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;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

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: rs955437777; hg19: chrX-46359469;