X-46500705-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001190417.2(ZNF674):c.869T>C(p.Leu290Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000042 (0 hom. 30 hem.)
  • Failed GnomAD Quality Control
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28477395).
• BS2: High Hemizygotes in GnomAdExome at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.869T>C	p.Leu290Pro	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.884T>C	p.Leu295Pro	missense_variant	6/6
ZNF674	NM_001146291.2	c.866T>C	p.Leu289Pro	missense_variant	6/6
ZNF674	XM_011543943.4	c.881T>C	p.Leu294Pro	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.869T>C	p.Leu290Pro	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.884T>C	p.Leu295Pro	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.866T>C	p.Leu289Pro	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000607 AC: 11 AN: 181266 Hom.: 0 AF XY: 0.000150 AC XY: 10 AN XY: 66848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000526

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000419 AC: 46 AN: 1097913 Hom.: 0 Cov.: 31 AF XY: 0.0000826 AC XY: 30 AN XY: 363317

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.000132 AC: 16

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 06, 2023

The c.884T>C (p.L295P) 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 884, causing the leucine (L) at amino acid position 295 to be replaced by a proline (P). 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	0.99
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.27
MutPred		0.76		Loss of stability (P = 0.0092);.;
MVP		0.87
MPC		1.0
ClinPred		0.51	D
GERP RS		2.0
Varity_R		0.84
gMVP		0.63

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: rs775076231; hg19: chrX-46360140;