Genetic Variant ITIH6:p.Arg1240His (chrX-54751014-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_198510.3(ITIH6):c.3719G>A(p.Arg1240His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,158,890 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000028 ( 0 hom. 14 hem. )

Consequence

ITIH6
NM_198510.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.239

Variant links:

Genes affected

ITIH6 (HGNC:28907): (inter-alpha-trypsin inhibitor heavy chain family member 6) The protein encoded by this gene belongs to the interalpha trypsin inhibitor heavy chain (ITIH) family. Interalpha trypsin inhibitor (ITI) is composed of two heavy chains (containing VWA domain) and one light chain. The light chain confers the protease-inhibitor function, while the heavy chains are involved in mediating protein-protein interactions with the components of the extracellular matrix. [provided by RefSeq, Sep 2009]

ITIH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045235902).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH6	NM_198510.3 link	c.3719G>A	p.Arg1240His	missense_variant	Exon 12 of 13	ENST00000218436.7	NP_940912.1	Q6UXX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH6	ENST00000218436.7 link	c.3719G>A	p.Arg1240His	missense_variant	Exon 12 of 13	1	NM_198510.3	ENSP00000218436.6		Q6UXX5

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112192

Hom.:

Cov.:

AF XY:

0.0000873

AC XY:

AN XY:

34356

show subpopulations

Gnomad AFR

AF:

0.000356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000940

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000554

AC:

AN:

108305

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

27379

show subpopulations

Gnomad AFR exome

AF:

0.000481

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000198

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1046698

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

334846

show subpopulations

Gnomad4 AFR exome

AF:

0.000473

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000354

Gnomad4 SAS exome

AF:

0.000168

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000981

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000107

AC:

AN:

112192

Hom.:

Cov.:

AF XY:

0.0000873

AC XY:

AN XY:

34356

show subpopulations

Gnomad4 AFR

AF:

0.000356

Gnomad4 AMR

AF:

0.0000940

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000525

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000267

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3719G>A (p.R1240H) alteration is located in exon 12 (coding exon 12) of the ITIH6 gene. This alteration results from a G to A substitution at nucleotide position 3719, causing the arginine (R) at amino acid position 1240 to be replaced by a histidine (H). 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

0.072

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.013

DANN

Benign

0.45

DEOGEN2

Benign

0.0032

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.53

M_CAP

Benign

0.0045

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.41

PROVEAN

Benign

1.1

REVEL

Benign

0.059

Sift

Benign

1.0

Sift4G

Benign

0.27

Polyphen

0.0030

Vest4

0.068

MVP

0.43

MPC

0.0079

ClinPred

0.025

GERP RS

-4.4

Varity_R

0.025

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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