X-46500823-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.751G>A(p.Glu251Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,190,032 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. 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: 𝑓 0.00026 (0 hom., 8 hem., cov: 22)
  • Exomes 𝑓: 0.000026 (0 hom. 4 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.347

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=0.019875497).
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.751G>A	p.Glu251Lys	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.766G>A	p.Glu256Lys	missense_variant	6/6
ZNF674	NM_001146291.2	c.748G>A	p.Glu250Lys	missense_variant	6/6
ZNF674	XM_011543943.4	c.763G>A	p.Glu255Lys	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.751G>A	p.Glu251Lys	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.766G>A	p.Glu256Lys	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.748G>A	p.Glu250Lys	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 28 AN: 109476 Hom.: 0 Cov.: 22 AF XY: 0.000252 AC XY: 8 AN XY: 31756

Gnomad AFR AF: 0.000766

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.000406

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000972 AC: 15 AN: 154314 Hom.: 0 AF XY: 0.0000207 AC XY: 1 AN XY: 48374

Gnomad AFR exome AF: 0.000937

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000259 AC: 28 AN: 1080501 Hom.: 0 Cov.: 30 AF XY: 0.0000114 AC XY: 4 AN XY: 350561

Gnomad4 AFR exome AF: 0.000500

Gnomad4 AMR exome AF: 0.0000927

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000570

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000601

Gnomad4 OTH exome AF: 0.0000880

GnomAD4 genome AF: 0.000256 AC: 28 AN: 109531 Hom.: 0 Cov.: 22 AF XY: 0.000251 AC XY: 8 AN XY: 31821

Gnomad4 AFR AF: 0.000764

Gnomad4 AMR AF: 0.000294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000285

Gnomad4 SAS AF: 0.000407

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.000298 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000839 AC: 10

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 10, 2023

The c.766G>A (p.E256K) 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 766, causing the glutamic acid (E) at amino acid position 256 to be replaced by a lysine (K). 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	0.20
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.034	T;.
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.064
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.35	B;.
Vest4		0.071
MVP		0.36
MPC		0.38
ClinPred		0.021	T
GERP RS		1.3
Varity_R		0.11
gMVP		0.11

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: rs368179569; hg19: chrX-46360258; COSMIC: COSV70379283; COSMIC: COSV70379283;