6-12120880-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002114.4(HIVEP1):c.1085C>T(p.Pro362Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,614,122 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (41 hom.)
• Consequence: HIVEP1 NM_002114.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84

Genes affected

HIVEP1 (HGNC:4920): (HIVEP zinc finger 1) This gene encodes a transcription factor belonging to the ZAS family, members of which are large proteins that contain a ZAS domain - a modular protein structure consisting of a pair of C2H2 zinc fingers with an acidic-rich region and a serine/threonine-rich sequence. These proteins bind specifically to the DNA sequence motif, GGGACTTTCC, found in the enhancer elements of several viral promoters, including human immunodeficiency virus (HIV), and to related sequences found in the enhancer elements of a number of cellular promoters. This protein binds to this sequence motif, suggesting a role in the transcriptional regulation of both viral and cellular genes. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018902123).
• BP6: Variant 6-12120880-C-T is Benign according to our data. Variant chr6-12120880-C-T is described in ClinVar as [Benign]. Clinvar id is 708914.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1805/152254) while in subpopulation AFR AF= 0.0408 (1693/41544). AF 95% confidence interval is 0.0391. There are 33 homozygotes in gnomad4. There are 850 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1801 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIVEP1	NM_002114.4	c.1085C>T	p.Pro362Leu	missense_variant	4/9	ENST00000379388.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIVEP1	ENST00000379388.7	c.1085C>T	p.Pro362Leu	missense_variant	4/9	1	NM_002114.4	P2
HIVEP1	ENST00000541134.5	c.1085C>T	p.Pro362Leu	missense_variant	4/9	5		A2
HIVEP1	ENST00000627968.2	c.-5219C>T		5_prime_UTR_variant	4/8	5
HIVEP1	ENST00000442081.6	c.166+946C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1801 AN: 152136 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00309 AC: 771 AN: 249514 Hom.: 14 AF XY: 0.00214 AC XY: 290 AN XY: 135360

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.00130 AC: 1903 AN: 1461868 Hom.: 41 Cov.: 37 AF XY: 0.00113 AC XY: 825 AN XY: 727234

Gnomad4 AFR exome AF: 0.0446

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000863

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.0119 AC: 1805 AN: 152254 Hom.: 33 Cov.: 32 AF XY: 0.0114 AC XY: 850 AN XY: 74434

Gnomad4 AFR AF: 0.0408

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00211 Hom.: 9

Bravo AF: 0.0140

ESP6500AA AF: 0.0407 AC: 165

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.00361 AC: 437

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	18
Dann	Benign	0.90
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.73	T;.
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
Sift4G	Uncertain	0.044	D;D
Vest4		0.050
MVP		0.23
MPC		0.095
ClinPred		0.024	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.28

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: rs34221818; hg19: chr6-12121113; COSMIC: COSV65103533; COSMIC: COSV65103533;