rs2710323

chr3-52781889-T-Cchr3-52781889-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002215.4(ITIH1):c.688-51T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,596,922 control chromosomes in the GnomAD database, including 188,005 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.53 (22443 hom., cov: 31)
  • Exomes 𝑓: 0.47 (165562 hom.)
• Consequence: ITIH1 NM_002215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

Genes affected

ITIH1 (HGNC:6166): (inter-alpha-trypsin inhibitor heavy chain 1) This gene encodes a member of the inter-alpha-trypsin inhibitor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the heavy chain of the inter-alpha-trypsin inhibitor complex, which is secreted by hepatocytes into the blood. The heavy chain also interacts with hyaluronan, and this interaction may play a role in ovulation and fertilization, and has been implicated in multiple inflammatory diseases. This gene is present in a gene cluster on chromosome 3. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH1	NM_002215.4	c.688-51T>C		intron_variant		ENST00000273283.7
ITIH1	NM_001166434.3	c.262-51T>C		intron_variant
ITIH1	NM_001166435.2	c.-177-51T>C		intron_variant
ITIH1	NM_001166436.2	c.-177-51T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH1	ENST00000273283.7	c.688-51T>C		intron_variant		1	NM_002215.4	P1

Frequencies

GnomAD3 genomes AF: 0.534 AC: 81147 AN: 151840 Hom.: 22407 Cov.: 31

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.520

GnomAD3 exomes AF: 0.488 AC: 119727 AN: 245388 Hom.: 30406 AF XY: 0.473 AC XY: 62785 AN XY: 132690

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.398

Gnomad SAS exome AF: 0.308

Gnomad FIN exome AF: 0.473

Gnomad NFE exome AF: 0.489

Gnomad OTH exome AF: 0.480

GnomAD4 exome AF: 0.474 AC: 685533 AN: 1444964 Hom.: 165562 Cov.: 32 AF XY: 0.469 AC XY: 335598 AN XY: 716088

Gnomad4 AFR exome AF: 0.678

Gnomad4 AMR exome AF: 0.610

Gnomad4 ASJ exome AF: 0.505

Gnomad4 EAS exome AF: 0.466

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.472

Gnomad4 NFE exome AF: 0.476

Gnomad4 OTH exome AF: 0.470

GnomAD4 genome AF: 0.535 AC: 81245 AN: 151958 Hom.: 22443 Cov.: 31 AF XY: 0.530 AC XY: 39350 AN XY: 74266

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.587

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.416

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.454

Gnomad4 NFE AF: 0.483

Gnomad4 OTH AF: 0.524

Alfa AF: 0.494 Hom.: 12570

Bravo AF: 0.555

Asia WGS AF: 0.428 AC: 1488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	8.8
Dann	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2710323; hg19: chr3-52815905; COSMIC: COSV56254435; COSMIC: COSV56254435;