3-52818164-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_002218.5(ITIH4):c.2184C>T(p.Pro728=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,611,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: ITIH4 NM_002218.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.692

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-52818164-G-A is Benign according to our data. Variant chr3-52818164-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 748950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.692 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH4	NM_002218.5	c.2184C>T	p.Pro728=	synonymous_variant	20/24	ENST00000266041.9
ITIH4	NM_001166449.2	c.2094C>T	p.Pro698=	synonymous_variant	18/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH4	ENST00000266041.9	c.2184C>T	p.Pro728=	synonymous_variant	20/24	1	NM_002218.5	P2

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 113 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000198 AC: 49 AN: 247516 Hom.: 0 AF XY: 0.000134 AC XY: 18 AN XY: 134274

Gnomad AFR exome AF: 0.00293

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000631 AC: 92 AN: 1458978 Hom.: 0 Cov.: 33 AF XY: 0.0000496 AC XY: 36 AN XY: 725438

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74498

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000603 Hom.: 0

Bravo AF: 0.000801

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ITIH4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	5.9
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146853969; hg19: chr3-52852180;