rs587780526

Variant names:

• chrX-46500372-A-G
• rs587780526
• NM_001190417.2:c.1202T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001190417.2(ZNF674):​c.1202T>C​(p.Ile401Thr) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00500
• 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=0.11451754).
• BP6: Variant X-46500372-A-G is Benign according to our data. Variant chrX-46500372-A-G is described in ClinVar as Benign. ClinVar VariationId is 130844.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	NM_001190417.2	MANE Select	c.1202T>C	p.Ile401Thr	missense	Exon 6 of 6	NP_001177346.1
	ZNF674	NM_001039891.3		c.1217T>C	p.Ile406Thr	missense	Exon 6 of 6	NP_001034980.1
	ZNF674	NM_001146291.2		c.1199T>C	p.Ile400Thr	missense	Exon 6 of 6	NP_001139763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	ENST00000683375.1	MANE Select	c.1202T>C	p.Ile401Thr	missense	Exon 6 of 6	ENSP00000506769.1
	ZNF674	ENST00000523374.5	TSL:1	c.1217T>C	p.Ile406Thr	missense	Exon 6 of 6	ENSP00000429148.1
	ZNF674	ENST00000414387.6	TSL:3	c.1199T>C	p.Ile400Thr	missense	Exon 5 of 5	ENSP00000428248.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000739 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	7.3
DANN	Benign	0.81
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Benign	0.00029	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.21	N
PhyloP100		0.0050
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.055
Sift	Benign	0.40	T
Sift4G	Benign	0.71	T
Polyphen		0.35	B
Vest4		0.095
MutPred		0.53		Loss of stability (P = 0.002)
MVP		0.61
MPC		0.28
ClinPred		0.032	T
GERP RS		1.0
Varity_R		0.14
gMVP		0.029
Mutation Taster		=98/2	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: rs587780526; hg19: chrX-46359807;