X-46499893-A-G

Variant names:

• chrX-46499893-A-G
• rs372786285
• NM_001190417.2:c.1681T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001190417.2(ZNF674):​c.1681T>C​(p.Ser561Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,049,689 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 0.000015 (0 hom. 6 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.127
• Publications: 0 publications found

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]

ZNF674 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: Ambry Genetics
• X-linked intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15720704).
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2	c.1681T>C	p.Ser561Pro	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3	c.1696T>C	p.Ser566Pro	missense_variant	Exon 6 of 6		NP_001034980.1
ZNF674	NM_001146291.2	c.1678T>C	p.Ser560Pro	missense_variant	Exon 6 of 6		NP_001139763.1
ZNF674	XM_011543943.4	c.1693T>C	p.Ser565Pro	missense_variant	Exon 6 of 6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF674	ENST00000683375.1	c.1681T>C	p.Ser561Pro	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1
ZNF674	ENST00000523374.5	c.1696T>C	p.Ser566Pro	missense_variant	Exon 6 of 6	1		ENSP00000429148.1
ZNF674	ENST00000414387.6	c.1678T>C	p.Ser560Pro	missense_variant	Exon 5 of 5	3		ENSP00000428248.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000219 AC: 3 AN: 136836 AF XY: 0.0000513

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000476

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000152 AC: 16 AN: 1049689 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 6 AN XY: 335853

African (AFR) AF: 0.00 AC: 0 AN: 24804

American (AMR) AF: 0.0000351 AC: 1 AN: 28511

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16408

East Asian (EAS) AF: 0.00 AC: 0 AN: 29736

South Asian (SAS) AF: 0.00 AC: 0 AN: 45355

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 0.0000183 AC: 15 AN: 818576

Other (OTH) AF: 0.00 AC: 0 AN: 44005

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000150 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 18, 2014

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S566P variant (also known as c.1696T>C), located in coding exon 4 of the ZNF674 gene, results from a T to C substitution at nucleotide position 1696. The serine at codon 566 is replaced by proline, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs372786285. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele was absent out of 2427 total male alleles studied. This amino acid position is not conserved on limited species alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.045	T;.
FATHMM_MKL	Benign	0.000070	N
LIST_S2	Benign	0.21	T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		-0.13
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.17
MVP		0.66
MPC		0.91
ClinPred		0.31	T
GERP RS		-0.041
Varity_R		0.68
gMVP		0.16
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs372786285; hg19: chrX-46359328;