Genetic Variant NM_002215.4:c.688-51T>C (chr3-52781889-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002215.4(ITIH1):c.688-51T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,596,922 control chromosomes in the GnomAD database, including 188,005 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.53 ( 22443 hom., cov: 31)

Exomes 𝑓: 0.47 ( 165562 hom. )

Consequence

ITIH1
NM_002215.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.00

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ITIH1	NM_002215.4 link	c.688-51T>C	intron_variant	Intron 6 of 21	ENST00000273283.7	NP_002206.2	P19827-1
ITIH1	NM_001166434.3 link	c.262-51T>C	intron_variant	Intron 4 of 19		NP_001159906.1	P19827-2
ITIH1	NM_001166435.2 link	c.-177-51T>C	intron_variant	Intron 2 of 17		NP_001159907.1	P19827-3
ITIH1	NM_001166436.2 link	c.-177-51T>C	intron_variant	Intron 2 of 17		NP_001159908.1	B7Z8B6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH1	ENST00000273283.7 link	c.688-51T>C		intron_variant	Intron 6 of 21	1	NM_002215.4	ENSP00000273283.2		P19827-1

Frequencies

GnomAD3 genomes

AF:

0.534

AC:

81147

AN:

151840

Hom.:

22407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.664

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.588

Gnomad ASJ

AF:

0.500

Gnomad EAS

AF:

0.417

Gnomad SAS

AF:

0.303

Gnomad FIN

AF:

0.454

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.483

Gnomad OTH

AF:

0.520

GnomAD3 exomes

AF:

0.488

AC:

119727

AN:

245388

Hom.:

30406

AF XY:

0.473

AC XY:

62785

AN XY:

132690

show subpopulations

Gnomad AFR exome

AF:

0.667

Gnomad AMR exome

AF:

0.617

Gnomad ASJ exome

AF:

0.495

Gnomad EAS exome

AF:

0.398

Gnomad SAS exome

AF:

0.308

Gnomad FIN exome

AF:

0.473

Gnomad NFE exome

AF:

0.489

Gnomad OTH exome

AF:

0.480

GnomAD4 exome

AF:

0.474

AC:

685533

AN:

1444964

Hom.:

165562

Cov.:

AF XY:

0.469

AC XY:

335598

AN XY:

716088

show subpopulations

Gnomad4 AFR exome

AF:

0.678

Gnomad4 AMR exome

AF:

0.610

Gnomad4 ASJ exome

AF:

0.505

Gnomad4 EAS exome

AF:

0.466

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.472

Gnomad4 NFE exome

AF:

0.476

Gnomad4 OTH exome

AF:

0.470

GnomAD4 genome

AF:

0.535

AC:

81245

AN:

151958

Hom.:

22443

Cov.:

AF XY:

0.530

AC XY:

39350

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.665

Gnomad4 AMR

AF:

0.587

Gnomad4 ASJ

AF:

0.500

Gnomad4 EAS

AF:

0.416

Gnomad4 SAS

AF:

0.302

Gnomad4 FIN

AF:

0.454

Gnomad4 NFE

AF:

0.483

Gnomad4 OTH

AF:

0.524

Alfa

AF:

0.494

Hom.:

12570

Bravo

AF:

0.555

Asia WGS

AF:

0.428

AC:

1488

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

8.8

DANN

Benign

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over