chr3-52826920-C-T

Variant names:

• chr3-52826920-C-T
• rs2276817
• NM_002218.5:c.390G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_002218.5(ITIH4):​c.390G>A​(p.Val130Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,872 control chromosomes in the GnomAD database, including 47,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (4842 hom., cov: 32)
  • Exomes 𝑓: 0.23 (42633 hom.)
• Consequence: ITIH4 NM_002218.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0210
• Publications: 48 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-52826920-C-T is Benign according to our data. Variant chr3-52826920-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060681.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.021 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002218.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH4	NM_002218.5	MANE Select	c.390G>A	p.Val130Val	synonymous	Exon 4 of 24	NP_002209.2
	ITIH4	NM_001166449.2		c.390G>A	p.Val130Val	synonymous	Exon 4 of 22	NP_001159921.1	Q14624-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH4	ENST00000266041.9	TSL:1 MANE Select	c.390G>A	p.Val130Val	synonymous	Exon 4 of 24	ENSP00000266041.4	Q14624-1
	ITIH4	ENST00000485816.5	TSL:1	c.390G>A	p.Val130Val	synonymous	Exon 4 of 24	ENSP00000417824.1	B7ZKJ8
	ENSG00000243696	ENST00000468472.1	TSL:2	n.*522G>A		non_coding_transcript_exon	Exon 9 of 24	ENSP00000422253.1	D6R8Y8

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37278 AN: 151960 Hom.: 4841 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.262 AC: 65839 AN: 251380 AF XY: 0.248

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.309

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.234 AC: 342172 AN: 1461794 Hom.: 42633 Cov.: 37 AF XY: 0.230 AC XY: 167258 AN XY: 727200

African (AFR) AF: 0.201 AC: 6728 AN: 33478

American (AMR) AF: 0.458 AC: 20485 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8401 AN: 26134

East Asian (EAS) AF: 0.348 AC: 13833 AN: 39700

South Asian (SAS) AF: 0.119 AC: 10251 AN: 86256

European-Finnish (FIN) AF: 0.256 AC: 13650 AN: 53360

Middle Eastern (MID) AF: 0.224 AC: 1290 AN: 5768

European-Non Finnish (NFE) AF: 0.228 AC: 253843 AN: 1111986

Other (OTH) AF: 0.227 AC: 13691 AN: 60390

GnomAD4 genome AF: 0.245 AC: 37299 AN: 152078 Hom.: 4842 Cov.: 32 AF XY: 0.247 AC XY: 18362 AN XY: 74324

African (AFR) AF: 0.208 AC: 8634 AN: 41502

American (AMR) AF: 0.374 AC: 5721 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1084 AN: 3466

East Asian (EAS) AF: 0.320 AC: 1652 AN: 5158

South Asian (SAS) AF: 0.129 AC: 619 AN: 4810

European-Finnish (FIN) AF: 0.258 AC: 2727 AN: 10588

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15909 AN: 67948

Other (OTH) AF: 0.246 AC: 518 AN: 2108

Alfa AF: 0.246 Hom.: 8273

Bravo AF: 0.256

Asia WGS AF: 0.237 AC: 822 AN: 3478

EpiCase AF: 0.237

EpiControl AF: 0.230

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ITIH4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.2
DANN	Benign	0.88
PhyloP100		-0.021
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2276817; hg19: chr3-52860936; COSMIC: COSV56579173; COSMIC: COSV56579173;