Variant chr3-52777638-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002215.4(ITIH1):c.23G>A(p.Arg8Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000753 in 1,593,006 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

ITIH1
NM_002215.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00500

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034893274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH1	NM_002215.4 linkuse as main transcript	c.23G>A	p.Arg8Gln	missense_variant	1/22	ENST00000273283.7	NP_002206.2	P19827-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH1	ENST00000273283.7 linkuse as main transcript	c.23G>A	p.Arg8Gln	missense_variant	1/22	1	NM_002215.4	ENSP00000273283.2		P19827-1
ITIH1	ENST00000480409.1 linkuse as main transcript	n.23G>A		non_coding_transcript_exon_variant	1/6	5		ENSP00000417340.1		F8WAS2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000994

AC:

AN:

231340

Hom.:

AF XY:

0.000145

AC XY:

AN XY:

124492

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.000533

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000473

Gnomad OTH exome

AF:

0.000178

GnomAD4 exome

AF:

0.0000770

AC:

111

AN:

1440752

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

715420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000611

Gnomad4 AMR exome

AF:

0.0000244

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000379

Gnomad4 SAS exome

AF:

0.000767

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000209

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.23G>A (p.R8Q) alteration is located in exon 1 (coding exon 1) of the ITIH1 gene. This alteration results from a G to A substitution at nucleotide position 23, causing the arginine (R) at amino acid position 8 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.73

M_CAP

Benign

0.010

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.77

REVEL

Benign

0.015

Sift

Benign

0.099

Sift4G

Benign

0.11

Polyphen

0.0030

Vest4

0.26

MVP

0.19

MPC

0.18

ClinPred

0.028

GERP RS

0.84

Varity_R

0.046

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over