3-52816983-A-G

Position:

• chr3-52816983-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002218.5(ITIH4):​c.2372T>C​(p.Leu791Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,613,840 control chromosomes in the GnomAD database, including 5,169 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 Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (2657 hom., cov: 33)
  • Exomes 𝑓: 0.011 (2512 hom.)
• Consequence: ITIH4 NM_002218.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.185

Genes affected

ITIH4 (HGNC:6169): (inter-alpha-trypsin inhibitor heavy chain 4) The protein encoded by this gene is secreted into the blood, where it is cleaved by plasma kallikrein into two smaller forms. Expression of this gene has been detected only in liver, and it seems to be upregulated during surgical trauma. This gene is part of a cluster of similar genes on chromosome 3. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ENSG00000243696 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009418458).
• BP6: Variant 3-52816983-A-G is Benign according to our data. Variant chr3-52816983-A-G is described in ClinVar as [Benign]. Clinvar id is 3059492.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH4	NM_002218.5	c.2372T>C	p.Leu791Pro	missense_variant	21/24	ENST00000266041.9	NP_002209.2
ITIH4	NM_001166449.2	c.2282T>C	p.Leu761Pro	missense_variant	19/22		NP_001159921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH4	ENST00000266041.9	c.2372T>C	p.Leu791Pro	missense_variant	21/24	1	NM_002218.5	ENSP00000266041.4
ENSG00000243696	ENST00000468472.1	n.*4008T>C		non_coding_transcript_exon_variant	21/24	2		ENSP00000422253.1
ENSG00000243696	ENST00000468472.1	n.*4008T>C		3_prime_UTR_variant	21/24	2		ENSP00000422253.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15434 AN: 152078 Hom.: 2645 Cov.: 33

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.0636

GnomAD3 exomes AF: 0.0263 AC: 6613 AN: 251340 Hom.: 1075 AF XY: 0.0195 AC XY: 2648 AN XY: 135834

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0107 AC: 15598 AN: 1461646 Hom.: 2512 Cov.: 32 AF XY: 0.00927 AC XY: 6739 AN XY: 727138

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000528

Gnomad4 OTH exome AF: 0.0231

GnomAD4 genome AF: 0.102 AC: 15471 AN: 152194 Hom.: 2657 Cov.: 33 AF XY: 0.0983 AC XY: 7316 AN XY: 74414

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0504 Hom.: 748

Bravo AF: 0.117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.341 AC: 1501

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0329 AC: 3997

Asia WGS AF: 0.0230 AC: 83 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ITIH4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.6
DANN	Benign	0.27
DEOGEN2	Benign	0.038	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.14	T;T;T
MetaRNN	Benign	0.0094	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.1	N;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	2.0	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.12
MPC		0.44
ClinPred		0.0034	T
GERP RS		3.0
Varity_R		0.041
gMVP		0.47

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: rs2535621; hg19: chr3-52850999;