chr3-52813481-C-A

Position:

• chr3-52813481-C-A

Variant summary

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

The NM_002218.5(ITIH4):​c.2733G>T​(p.Arg911Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITIH4 NM_002218.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.215

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]

ENSG00000243696 (HGNC:):

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=0.27795345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH4	NM_002218.5	c.2733G>T	p.Arg911Ser	missense_variant	24/24	ENST00000266041.9	NP_002209.2
ITIH4	NM_001166449.2	c.2643G>T	p.Arg881Ser	missense_variant	22/22		NP_001159921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH4	ENST00000266041.9	c.2733G>T	p.Arg911Ser	missense_variant	24/24	1	NM_002218.5	ENSP00000266041.4
ENSG00000243696	ENST00000468472.1	n.*4369G>T		non_coding_transcript_exon_variant	24/24	2		ENSP00000422253.1
ENSG00000243696	ENST00000468472.1	n.*4369G>T		3_prime_UTR_variant	24/24	2		ENSP00000422253.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461692 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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 10, 2024

The c.2733G>T (p.R911S) alteration is located in exon 24 (coding exon 24) of the ITIH4 gene. This alteration results from a G to T substitution at nucleotide position 2733, causing the arginine (R) at amino acid position 911 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	0.30
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.089
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.035	D;D;T
Polyphen		0.093	B;B;.
Vest4		0.083
MutPred		0.70		.;Gain of glycosylation at Y919 (P = 0.0023);.;
MVP		0.45
MPC		0.39
ClinPred		0.48	T
GERP RS		3.4
Varity_R		0.21
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr3-52847497;