3-52814338-C-T

Position:

• chr3-52814338-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002218.5(ITIH4):​c.2497G>A​(p.Gly833Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITIH4 NM_002218.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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]

ACMG classification

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=0.3573887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH4	NM_002218.5	c.2497G>A	p.Gly833Ser	missense_variant	22/24	ENST00000266041.9	NP_002209.2
ITIH4	NM_001166449.2	c.2407G>A	p.Gly803Ser	missense_variant	20/22		NP_001159921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH4	ENST00000266041.9	c.2497G>A	p.Gly833Ser	missense_variant	22/24	1	NM_002218.5	ENSP00000266041	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.2497G>A (p.G833S) alteration is located in exon 22 (coding exon 22) of the ITIH4 gene. This alteration results from a G to A substitution at nucleotide position 2497, causing the glycine (G) at amino acid position 833 to be replaced by a serine (S). 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	0.18
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.083	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.050	D;D;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.99	D;D;.
Vest4		0.30
MutPred		0.43		.;Gain of sheet (P = 0.0043);.;
MVP		0.54
MPC		0.93
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.089
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52848354;