Genetic Variant ITIH6:p.His1248His (chrX-54750093-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_198510.3(ITIH6):c.3744C>T(p.His1248His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,203,674 control chromosomes in the GnomAD database, including 1 homozygotes. There are 141 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.00038 ( 1 hom. 134 hem. )

Consequence

ITIH6
NM_198510.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.279

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant X-54750093-G-A is Benign according to our data. Variant chrX-54750093-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2660671.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.279 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH6	NM_198510.3 link	c.3744C>T	p.His1248His	synonymous_variant	Exon 13 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.3744C>T	p.His1248His	synonymous_variant	Exon 13 of 13	1	NM_198510.3	ENSP00000218436.6		Q6UXX5

Frequencies

GnomAD3 genomes

AF:

0.000268

AC:

AN:

111836

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

33986

show subpopulations

Gnomad AFR

AF:

0.0000977

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000473

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000381

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000395

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000232

AC:

AN:

176407

Hom.:

AF XY:

0.000179

AC XY:

AN XY:

61327

show subpopulations

Gnomad AFR exome

AF:

0.000386

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000318

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.000377

AC:

412

AN:

1091786

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

134

AN XY:

357604

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000150

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000457

Gnomad4 OTH exome

AF:

0.000240

GnomAD4 genome

AF:

0.000268

AC:

AN:

111888

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

34048

show subpopulations

Gnomad4 AFR

AF:

0.0000975

Gnomad4 AMR

AF:

0.000473

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000383

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000395

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000242

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ITIH6: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.21

DANN

Benign

0.39

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