Variant 3-52814260-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002218.5(ITIH4):c.2575C>T(p.Leu859Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITIH4
NM_002218.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48

Variant links:

Genes affected

ITIH4 (HGNC:6169): (inter-alpha-trypsin inhibitor heavy chain 4) The protein encoded by this gene is secreted into the blood, where it is cleaved by plasma kallikrein into two smaller forms. Expression of this gene has been detected only in liver, and it seems to be upregulated during surgical trauma. This gene is part of a cluster of similar genes on chromosome 3. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ITIH4 links:

ENSG00000243696 (HGNC:):

ENSG00000243696 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33850837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH4	NM_002218.5 linkuse as main transcript	c.2575C>T	p.Leu859Phe	missense_variant	22/24	ENST00000266041.9	NP_002209.2	Q14624-1B7ZKJ8B2RMS9
ITIH4	NM_001166449.2 linkuse as main transcript	c.2485C>T	p.Leu829Phe	missense_variant	20/22		NP_001159921.1	Q14624-3B7ZKJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITIH4	ENST00000266041.9 linkuse as main transcript	c.2575C>T	p.Leu859Phe	missense_variant	22/24	1	NM_002218.5	ENSP00000266041.4	Q14624-1
ENSG00000243696	ENST00000468472.1 linkuse as main transcript	n.*4211C>T		non_coding_transcript_exon_variant	22/24	2		ENSP00000422253.1	D6R8Y8
ENSG00000243696	ENST00000468472.1 linkuse as main transcript	n.*4211C>T		3_prime_UTR_variant	22/24	2		ENSP00000422253.1	D6R8Y8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461538

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 01, 2024

The c.2575C>T (p.L859F) alteration is located in exon 22 (coding exon 22) of the ITIH4 gene. This alteration results from a C to T substitution at nucleotide position 2575, causing the leucine (L) at amino acid position 859 to be replaced by a phenylalanine (F). 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

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.059

T;T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.41

T;T;T

Sift4G

Benign

0.42

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.41

MutPred

0.59

.;Gain of glycosylation at T869 (P = 0.0374);.;

MVP

0.36

MPC

0.98

ClinPred

0.84

GERP RS

4.1

Varity_R

0.049

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over