X-46500597-A-G

Variant names:

• chrX-46500597-A-G
• rs750888011
• NM_001190417.2:c.977T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001190417.2(ZNF674):​c.977T>C​(p.Ile326Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.387
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040827602).

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.977T>C	p.Ile326Thr	missense	Exon 6 of 6	NP_001177346.1	A0A804HHU7
	ZNF674	NM_001039891.3		c.992T>C	p.Ile331Thr	missense	Exon 6 of 6	NP_001034980.1	Q2M3X9-1
	ZNF674	NM_001146291.2		c.974T>C	p.Ile325Thr	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.977T>C	p.Ile326Thr	missense	Exon 6 of 6	ENSP00000506769.1	A0A804HHU7
	ZNF674	ENST00000523374.5	TSL:1	c.992T>C	p.Ile331Thr	missense	Exon 6 of 6	ENSP00000429148.1	Q2M3X9-1
	ZNF674	ENST00000878263.1		c.977T>C	p.Ile326Thr	missense	Exon 6 of 6	ENSP00000548322.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181530 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: 0.0000727

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000827 AC: 1

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	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.1
DANN	Benign	0.81
DEOGEN2	Benign	0.0025	T
FATHMM_MKL	Benign	0.000020	N
LIST_S2	Benign	0.089	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.39
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.079
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.60		Gain of disorder (P = 0.0308)
MVP		0.53
MPC		0.27
ClinPred		0.032	T
GERP RS		-0.37
Varity_R		0.033
gMVP		0.040
Mutation Taster		=100/0	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: rs750888011; hg19: chrX-46360032;