X-46500372-A-G

Position:

• chrX-46500372-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001190417.2(ZNF674):​c.1202T>C​(p.Ile401Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00500

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11451754).
• BP6: Variant X-46500372-A-G is Benign according to our data. Variant chrX-46500372-A-G is described in ClinVar as [Benign]. Clinvar id is 130844.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF674	NM_001190417.2	c.1202T>C	p.Ile401Thr	missense_variant	6/6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3	c.1217T>C	p.Ile406Thr	missense_variant	6/6		NP_001034980.1
ZNF674	NM_001146291.2	c.1199T>C	p.Ile400Thr	missense_variant	6/6		NP_001139763.1
ZNF674	XM_011543943.4	c.1214T>C	p.Ile405Thr	missense_variant	6/6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF674	ENST00000683375.1	c.1202T>C	p.Ile401Thr	missense_variant	6/6		NM_001190417.2	ENSP00000506769	A1
ZNF674	ENST00000523374.5	c.1217T>C	p.Ile406Thr	missense_variant	6/6	1		ENSP00000429148	P4
ZNF674	ENST00000414387.6	c.1199T>C	p.Ile400Thr	missense_variant	5/5	3		ENSP00000428248	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000302

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 10, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	7.3
DANN	Benign	0.81
DEOGEN2	Benign	0.016	T;.
FATHMM_MKL	Benign	0.00029	N
LIST_S2	Benign	0.18	T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.21	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.055
Sift	Benign	0.40	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.35	B;.
Vest4		0.095
MutPred		0.53		Loss of stability (P = 0.002);.;
MVP		0.61
MPC		0.28
ClinPred		0.032	T
GERP RS		1.0
Varity_R		0.14
gMVP		0.029

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: rs587780526; hg19: chrX-46359807;