rs3821831

chr3-52819385-C-T

Variant summary

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

The NM_002218.5(ITIH4):c.2077+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,613,340 control chromosomes in the GnomAD database, including 100,256 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.29 (7022 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93234 hom.)
• Consequence: ITIH4 NM_002218.5 splice_region, intron
• Scores: Splicing: ADA: 0.00007385
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.86

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 3-52819385-C-T is Benign according to our data. Variant chr3-52819385-C-T is described in ClinVar as [Benign]. Clinvar id is 9042.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH4	NM_002218.5	c.2077+8G>A		splice_region_variant, intron_variant		ENST00000266041.9
ITIH4	NM_001166449.2	c.1987+8G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH4	ENST00000266041.9	c.2077+8G>A		splice_region_variant, intron_variant		1	NM_002218.5	P2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43892 AN: 152040 Hom.: 7021 Cov.: 33

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.0776

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.291 AC: 73103 AN: 250812 Hom.: 11935 AF XY: 0.298 AC XY: 40433 AN XY: 135576

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.0734

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.341

Gnomad NFE exome AF: 0.377

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.349 AC: 510070 AN: 1461182 Hom.: 93234 Cov.: 37 AF XY: 0.347 AC XY: 252402 AN XY: 726896

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.170

Gnomad4 ASJ exome AF: 0.315

Gnomad4 EAS exome AF: 0.0688

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.346

Gnomad4 NFE exome AF: 0.379

Gnomad4 OTH exome AF: 0.330

GnomAD4 genome AF: 0.288 AC: 43890 AN: 152158 Hom.: 7022 Cov.: 33 AF XY: 0.284 AC XY: 21120 AN XY: 74388

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.0776

Gnomad4 SAS AF: 0.256

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.374

Gnomad4 OTH AF: 0.290

Alfa AF: 0.348 Hom.: 16891

Bravo AF: 0.272

Asia WGS AF: 0.165 AC: 577 AN: 3478

EpiCase AF: 0.370

EpiControl AF: 0.373

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypercholesterolemia, susceptibility to Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.037
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.030		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: rs3821831; hg19: chr3-52853401; COSMIC: COSV56571513; COSMIC: COSV56571513;