NM_002215.4:c.688-51T>C

Variant names:

• chr3-52781889-T-C
• rs2710323
• NM_002215.4:c.688-51T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 58 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ITIH1	NM_002215.4	c.688-51T>C		intron_variant	Intron 6 of 21	ENST00000273283.7	NP_002206.2
ITIH1	NM_001166434.3	c.262-51T>C		intron_variant	Intron 4 of 19		NP_001159906.1
ITIH1	NM_001166435.2	c.-177-51T>C		intron_variant	Intron 2 of 17		NP_001159907.1
ITIH1	NM_001166436.2	c.-177-51T>C		intron_variant	Intron 2 of 17		NP_001159908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH1	ENST00000273283.7	c.688-51T>C		intron_variant	Intron 6 of 21	1	NM_002215.4	ENSP00000273283.2

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

GnomAD2 exomes AF: 0.488 AC: 119727 AN: 245388 AF XY: 0.473

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 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

African (AFR) AF: 0.678 AC: 22490 AN: 33176

American (AMR) AF: 0.610 AC: 26820 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 13019 AN: 25802

East Asian (EAS) AF: 0.466 AC: 18304 AN: 39312

South Asian (SAS) AF: 0.307 AC: 26216 AN: 85472

European-Finnish (FIN) AF: 0.472 AC: 24486 AN: 51928

Middle Eastern (MID) AF: 0.484 AC: 2701 AN: 5576

European-Non Finnish (NFE) AF: 0.476 AC: 523479 AN: 1100126

Other (OTH) AF: 0.470 AC: 28018 AN: 59610

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

African (AFR) AF: 0.665 AC: 27542 AN: 41440

American (AMR) AF: 0.587 AC: 8969 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1734 AN: 3466

East Asian (EAS) AF: 0.416 AC: 2151 AN: 5166

South Asian (SAS) AF: 0.302 AC: 1455 AN: 4810

European-Finnish (FIN) AF: 0.454 AC: 4791 AN: 10544

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32825 AN: 67958

Other (OTH) AF: 0.524 AC: 1101 AN: 2100

Alfa AF: 0.503 Hom.: 44155

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
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2710323; hg19: chr3-52815905; COSMIC: COSV56254435; COSMIC: COSV56254435;