X-46500238-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001190417.2(ZNF674):c.1336G>A(p.Gly446Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000498 in 1,205,109 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.000029 (0 hom. 9 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.52

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014963359).
• BS2: High Hemizygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.1336G>A	p.Gly446Arg	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.1351G>A	p.Gly451Arg	missense_variant	6/6
ZNF674	NM_001146291.2	c.1333G>A	p.Gly445Arg	missense_variant	6/6
ZNF674	XM_011543943.4	c.1348G>A	p.Gly450Arg	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.1336G>A	p.Gly446Arg	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.1351G>A	p.Gly451Arg	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.1333G>A	p.Gly445Arg	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes AF: 0.000260 AC: 28 AN: 107549 Hom.: 0 Cov.: 23 AF XY: 0.000287 AC XY: 9 AN XY: 31319

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000698

GnomAD3 exomes AF: 0.0000827 AC: 15 AN: 181418 Hom.: 0 AF XY: 0.0000447 AC XY: 3 AN XY: 67130

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.0000730

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 AF: 0.0000292 AC: 32 AN: 1097502 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 9 AN XY: 362910

Gnomad4 AFR exome AF: 0.000947

Gnomad4 AMR exome AF: 0.0000568

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: 0.00000238

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.000260 AC: 28 AN: 107607 Hom.: 0 Cov.: 23 AF XY: 0.000287 AC XY: 9 AN XY: 31387

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000690

Alfa AF: 0.000144 Hom.: 1

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000989 AC: 12

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

Feb 27, 2024

The c.1351G>A (p.G451R) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a G to A substitution at nucleotide position 1351, causing the glycine (G) at amino acid position 451 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	Pathogenic	0.59
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	2.5
Dann	Benign	0.78
DEOGEN2	Benign	0.014	T;.
FATHMM_MKL	Benign	0.000020	N
LIST_S2	Benign	0.087	T;T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.67	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.044
Sift	Benign	0.20	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.14	B;.
Vest4		0.053
MutPred		0.35		Gain of MoRF binding (P = 0.0118);.;
MVP		0.57
MPC		0.84
ClinPred		0.063	T
GERP RS		-0.099
Varity_R		0.075
gMVP		0.081

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: rs373268159; hg19: chrX-46359673; COSMIC: COSV105345597; COSMIC: COSV105345597;