X-46500801-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001190417.2(ZNF674):c.773A>G(p.Gln258Arg) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.77

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10811955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.773A>G	p.Gln258Arg	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.788A>G	p.Gln263Arg	missense_variant	6/6
ZNF674	NM_001146291.2	c.770A>G	p.Gln257Arg	missense_variant	6/6
ZNF674	XM_011543943.4	c.785A>G	p.Gln262Arg	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.773A>G	p.Gln258Arg	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.788A>G	p.Gln263Arg	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.770A>G	p.Gln257Arg	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000187 AC: 3 AN: 160385 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 51183

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000276 AC: 3 AN: 1085252 Hom.: 0 Cov.: 30 AF XY: 0.00000283 AC XY: 1 AN XY: 353622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000603

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000189

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000250 AC: 3

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

Jun 23, 2023

The c.788A>G (p.Q263R) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a A to G substitution at nucleotide position 788, causing the glutamine (Q) at amino acid position 263 to be replaced by an arginine (R). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.017	T;.
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.072	T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.15	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.051
Sift	Benign	0.34	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.15	B;.
Vest4		0.036
MutPred		0.45		Gain of MoRF binding (P = 0.0256);.;
MVP		0.72
MPC		0.52
ClinPred		0.76	D
GERP RS		2.1
Varity_R		0.21
gMVP		0.033

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: rs768005975; hg19: chrX-46360236;