X-46500597-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001190417.2(ZNF674):c.977T>C(p.Ile326Thr) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.387

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=0.040827602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.977T>C	p.Ile326Thr	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.992T>C	p.Ile331Thr	missense_variant	6/6
ZNF674	NM_001146291.2	c.974T>C	p.Ile325Thr	missense_variant	6/6
ZNF674	XM_011543943.4	c.989T>C	p.Ile330Thr	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.977T>C	p.Ile326Thr	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.992T>C	p.Ile331Thr	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.974T>C	p.Ile325Thr	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181530 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000727

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2023

The c.992T>C (p.I331T) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a T to C substitution at nucleotide position 992, causing the isoleucine (I) at amino acid position 331 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.1
Dann	Benign	0.81
DEOGEN2	Benign	0.0025	T;.
FATHMM_MKL	Benign	0.000020	N
LIST_S2	Benign	0.089	T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.8	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.5	N;N
REVEL	Benign	0.079
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.11
MutPred		0.60		Gain of disorder (P = 0.0308);.;
MVP		0.53
MPC		0.27
ClinPred		0.032	T
GERP RS		-0.37
Varity_R		0.033
gMVP		0.040

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: rs750888011; hg19: chrX-46360032;