rs1042779

Variant names:

• chr3-52786995-A-G
• rs1042779
• NM_002215.4:c.1784A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002215.4(ITIH1):​c.1784A>G​(p.Gln595Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,613,346 control chromosomes in the GnomAD database, including 118,940 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.42 (13684 hom., cov: 32)
  • Exomes 𝑓: 0.38 (105256 hom.)
• Consequence: ITIH1 NM_002215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05
• Publications: 93 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 (MetaRNN=2.501905E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH1	NM_002215.4	c.1784A>G	p.Gln595Arg	missense_variant	Exon 14 of 22	ENST00000273283.7	NP_002206.2
ITIH1	NM_001166434.3	c.1358A>G	p.Gln453Arg	missense_variant	Exon 12 of 20		NP_001159906.1
ITIH1	NM_001166435.2	c.920A>G	p.Gln307Arg	missense_variant	Exon 10 of 18		NP_001159907.1
ITIH1	NM_001166436.2	c.920A>G	p.Gln307Arg	missense_variant	Exon 10 of 18		NP_001159908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH1	ENST00000273283.7	c.1784A>G	p.Gln595Arg	missense_variant	Exon 14 of 22	1	NM_002215.4	ENSP00000273283.2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63312 AN: 151724 Hom.: 13663 Cov.: 32

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.412

GnomAD2 exomes AF: 0.400 AC: 100376 AN: 251060 AF XY: 0.388

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.547

Gnomad ASJ exome AF: 0.439

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.382

GnomAD4 exome AF: 0.376 AC: 549549 AN: 1461504 Hom.: 105256 Cov.: 46 AF XY: 0.372 AC XY: 270549 AN XY: 727074

African (AFR) AF: 0.498 AC: 16659 AN: 33466

American (AMR) AF: 0.536 AC: 23938 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 11698 AN: 26128

East Asian (EAS) AF: 0.449 AC: 17810 AN: 39696

South Asian (SAS) AF: 0.274 AC: 23626 AN: 86248

European-Finnish (FIN) AF: 0.368 AC: 19677 AN: 53410

Middle Eastern (MID) AF: 0.426 AC: 2453 AN: 5762

European-Non Finnish (NFE) AF: 0.370 AC: 411105 AN: 1111726

Other (OTH) AF: 0.374 AC: 22583 AN: 60378

GnomAD4 genome AF: 0.417 AC: 63386 AN: 151842 Hom.: 13684 Cov.: 32 AF XY: 0.417 AC XY: 30926 AN XY: 74212

African (AFR) AF: 0.494 AC: 20467 AN: 41436

American (AMR) AF: 0.485 AC: 7397 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1508 AN: 3466

East Asian (EAS) AF: 0.386 AC: 1995 AN: 5162

South Asian (SAS) AF: 0.273 AC: 1313 AN: 4816

European-Finnish (FIN) AF: 0.357 AC: 3761 AN: 10548

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25544 AN: 67840

Other (OTH) AF: 0.417 AC: 881 AN: 2114

Alfa AF: 0.394 Hom.: 33908

Bravo AF: 0.434

TwinsUK AF: 0.357 AC: 1324

ALSPAC AF: 0.364 AC: 1401

ESP6500AA AF: 0.483 AC: 2127

ESP6500EA AF: 0.387 AC: 3330

ExAC AF: 0.398 AC: 48277

Asia WGS AF: 0.365 AC: 1265 AN: 3478

EpiCase AF: 0.388

EpiControl AF: 0.383

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.063	T;T;T
MetaRNN	Benign	0.00025	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.0	M;.;.
PhyloP100		3.0
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.063
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.018
MPC		0.16
ClinPred		0.0086	T
GERP RS		3.0
Varity_R		0.079
gMVP		0.21
Mutation Taster		=95/5	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: rs1042779; hg19: chr3-52821011; COSMIC: COSV56253693; COSMIC: COSV56253693;