rs141050437

Positions:

• chr6-142773706-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_006734.4(HIVEP2):​c.1033A>G​(p.Ile345Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,614,114 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (49 hom.)
• Consequence: HIVEP2 NM_006734.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.241

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HIVEP2. . Gene score misZ 1.8295 (greater than the threshold 3.09). Trascript score misZ 3.809 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 43.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025461614).
• BP6: Variant 6-142773706-T-C is Benign according to our data. Variant chr6-142773706-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 445442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-142773706-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 658 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIVEP2	NM_006734.4	c.1033A>G	p.Ile345Val	missense_variant	5/10	ENST00000367603.8	NP_006725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIVEP2	ENST00000367603.8	c.1033A>G	p.Ile345Val	missense_variant	5/10	1	NM_006734.4	ENSP00000356575.2

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 658 AN: 152174 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00489 AC: 1219 AN: 249520 Hom.: 18 AF XY: 0.00488 AC XY: 660 AN XY: 135382

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0308

Gnomad NFE exome AF: 0.00433

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00426 AC: 6232 AN: 1461822 Hom.: 49 Cov.: 34 AF XY: 0.00410 AC XY: 2981 AN XY: 727224

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0292

Gnomad4 NFE exome AF: 0.00396

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152292 Hom.: 5 Cov.: 32 AF XY: 0.00549 AC XY: 409 AN XY: 74460

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0339

Gnomad4 NFE AF: 0.00372

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00335 Hom.: 1

Bravo AF: 0.00198

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000530 AC: 2

ESP6500EA AF: 0.00341 AC: 28

ExAC AF: 0.00468 AC: 565

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	HIVEP2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.8
DANN	Benign	0.52
DEOGEN2	Benign	0.060	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.61	.;.;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.67	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.18	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.51	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.040
MVP		0.043
MPC		0.16
ClinPred		0.0045	T
GERP RS		-7.5
Varity_R		0.015
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs141050437; hg19: chr6-143094843;