3-52824921-T-C

Variant names:

• chr3-52824921-T-C
• NM_002218.5:c.797A>G

Variant summary

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

The NM_002218.5(ITIH4):​c.797A>G​(p.Glu266Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ITIH4 NM_002218.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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:):

ITIH4-AS1 (HGNC:40310): (ITIH4 antisense RNA 1)

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=0.34098896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH4	NM_002218.5	c.797A>G	p.Glu266Gly	missense_variant	Exon 7 of 24	ENST00000266041.9	NP_002209.2
ITIH4	NM_001166449.2	c.797A>G	p.Glu266Gly	missense_variant	Exon 7 of 22		NP_001159921.1
ITIH4-AS1	NR_046615.1	n.286-284T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH4	ENST00000266041.9	c.797A>G	p.Glu266Gly	missense_variant	Exon 7 of 24	1	NM_002218.5	ENSP00000266041.4
ENSG00000243696	ENST00000468472.1	n.*929A>G		non_coding_transcript_exon_variant	Exon 12 of 24	2		ENSP00000422253.1
ENSG00000243696	ENST00000468472.1	n.*929A>G		3_prime_UTR_variant	Exon 12 of 24	2		ENSP00000422253.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461632 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.797A>G (p.E266G) alteration is located in exon 7 (coding exon 7) of the ITIH4 gene. This alteration results from a A to G substitution at nucleotide position 797, causing the glutamic acid (E) at amino acid position 266 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;T;.
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.8	M;.;M
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.023	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.74	P;P;.
Vest4		0.26
MutPred		0.31		Loss of glycosylation at T269 (P = 0.0264);Loss of glycosylation at T269 (P = 0.0264);Loss of glycosylation at T269 (P = 0.0264);
MVP		0.81
MPC		0.79
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.24
gMVP		0.33

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: chr3-52858937;