chrX-46500524-C-G

Variant names:

• chrX-46500524-C-G
• rs748331751
• NM_001190417.2:c.1050G>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.1050G>C​(p.Glu350Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,097,663 control chromosomes in the GnomAD database, including 1 homozygotes. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 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 (1 hom. 6 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.244
• 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=0.12817839).
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190417.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	NM_001190417.2	MANE Select	c.1050G>C	p.Glu350Asp	missense	Exon 6 of 6	NP_001177346.1	A0A804HHU7
	ZNF674	NM_001039891.3		c.1065G>C	p.Glu355Asp	missense	Exon 6 of 6	NP_001034980.1	Q2M3X9-1
	ZNF674	NM_001146291.2		c.1047G>C	p.Glu349Asp	missense	Exon 6 of 6	NP_001139763.1	Q2M3X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	ENST00000683375.1	MANE Select	c.1050G>C	p.Glu350Asp	missense	Exon 6 of 6	ENSP00000506769.1	A0A804HHU7
	ZNF674	ENST00000523374.5	TSL:1	c.1065G>C	p.Glu355Asp	missense	Exon 6 of 6	ENSP00000429148.1	Q2M3X9-1
	ZNF674	ENST00000878263.1		c.1050G>C	p.Glu350Asp	missense	Exon 6 of 6	ENSP00000548322.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181103 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1097663 Hom.: 1 Cov.: 31 AF XY: 0.0000165 AC XY: 6 AN XY: 363097

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54133

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841657

Other (OTH) AF: 0.00 AC: 0 AN: 46066

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	T
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.24
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.063
Sift	Benign	0.046	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.070
MutPred		0.41		Gain of ubiquitination at K356 (P = 0.143)
MVP		0.27
MPC		0.19
ClinPred		0.082	T
GERP RS		1.8
Varity_R		0.12
gMVP		0.029
Mutation Taster		=95/5	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: rs748331751; hg19: chrX-46359959;