3-52786965-A-T

Position:

• chr3-52786965-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002215.4(ITIH1):​c.1754A>T​(p.Glu585Val) variant causes a missense change. The variant allele was found at a frequency of 0.35 in 1,612,586 control chromosomes in the GnomAD database, including 102,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8340 hom., cov: 33)
  • Exomes 𝑓: 0.35 (94567 hom.)
• Consequence: ITIH1 NM_002215.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.05

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]

ITIH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 3-52786965-A-T is Benign according to our data. Variant chr3-52786965-A-T is described in ClinVar as [Benign]. Clinvar id is 487489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH1	NM_002215.4	c.1754A>T	p.Glu585Val	missense_variant	14/22	ENST00000273283.7	NP_002206.2
ITIH1	NM_001166434.3	c.1328A>T	p.Glu443Val	missense_variant	12/20		NP_001159906.1
ITIH1	NM_001166435.2	c.890A>T	p.Glu297Val	missense_variant	10/18		NP_001159907.1
ITIH1	NM_001166436.2	c.890A>T	p.Glu297Val	missense_variant	10/18		NP_001159908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH1	ENST00000273283.7	c.1754A>T	p.Glu585Val	missense_variant	14/22	1	NM_002215.4	ENSP00000273283.2

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47383 AN: 151810 Hom.: 8339 Cov.: 33

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.337

GnomAD3 exomes AF: 0.358 AC: 89532 AN: 250182 Hom.: 17188 AF XY: 0.349 AC XY: 47179 AN XY: 135176

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.357

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.354 AC: 517462 AN: 1460658 Hom.: 94567 Cov.: 47 AF XY: 0.350 AC XY: 254097 AN XY: 726544

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.510

Gnomad4 ASJ exome AF: 0.445

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.362

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.312 AC: 47408 AN: 151928 Hom.: 8340 Cov.: 33 AF XY: 0.314 AC XY: 23280 AN XY: 74254

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.368

Gnomad4 OTH AF: 0.342

Alfa AF: 0.358 Hom.: 3527

Bravo AF: 0.315

TwinsUK AF: 0.350 AC: 1298

ALSPAC AF: 0.355 AC: 1368

ESP6500AA AF: 0.147 AC: 646

ESP6500EA AF: 0.379 AC: 3261

ExAC AF: 0.349 AC: 42390

Asia WGS AF: 0.300 AC: 1040 AN: 3478

EpiCase AF: 0.381

EpiControl AF: 0.372

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 30374069) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.51	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.014	D;D;T
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.21
MPC		0.71
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.61
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs678; hg19: chr3-52820981; COSMIC: COSV56251847; COSMIC: COSV56251847;