NM_006734.4:c.5461C>A

Variant names:

• chr6-142764856-G-T
• rs1554275655
• NM_006734.4:c.5461C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_006734.4(HIVEP2):​c.5461C>A​(p.His1821Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HIVEP2 NM_006734.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

HIVEP2 (HGNC:4921): (HIVEP zinc finger 2) This gene encodes a member of a family of closely related, large, zinc finger-containing transcription factors. The encoded protein regulates transcription by binding to regulatory regions of various cellular and viral genes that maybe involved in growth, development and metastasis. The protein contains the ZAS domain comprised of two widely separated regions of zinc finger motifs, a stretch of highly acidic amino acids and a serine/threonine-rich sequence. [provided by RefSeq, Nov 2012]

HIVEP2 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 43

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 6-142764856-G-T is Pathogenic according to our data. Variant chr6-142764856-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIVEP2	NM_006734.4	c.5461C>A	p.His1821Asn	missense_variant	Exon 7 of 10	ENST00000367603.8	NP_006725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIVEP2	ENST00000367603.8	c.5461C>A	p.His1821Asn	missense_variant	Exon 7 of 10	1	NM_006734.4	ENSP00000356575.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Aug 31, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.8	H;H;H
PhyloP100		10
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.81		Loss of catalytic residue at R1819 (P = 0.0636);Loss of catalytic residue at R1819 (P = 0.0636);Loss of catalytic residue at R1819 (P = 0.0636);
MVP		0.60
MPC		3.0
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.79
gMVP		0.90
Mutation Taster		=33/67	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554275655; hg19: chr6-143085993;