rs4687657

chr3-52818522-G-Achr3-52818522-G-Cchr3-52818522-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002218.5(ITIH4):c.2092C>T(p.Pro698Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,602,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P698T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: ITIH4 NM_002218.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.330

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106270194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH4	NM_002218.5	c.2092C>T	p.Pro698Ser	missense_variant	18/24	ENST00000266041.9
ITIH4	NM_001166449.2	c.2002C>T	p.Pro668Ser	missense_variant	16/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH4	ENST00000266041.9	c.2092C>T	p.Pro698Ser	missense_variant	18/24	1	NM_002218.5	P2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151890 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000317 AC: 46 AN: 1450518 Hom.: 0 Cov.: 34 AF XY: 0.0000361 AC XY: 26 AN XY: 720482

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000416

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74176

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.34
Dann	Benign	0.43
DEOGEN2	Benign	0.37	T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.030	D;D;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0050	B;B;.
Vest4		0.092
MutPred		0.22		.;Loss of glycosylation at P703 (P = 0.0064);.;
MVP		0.42
MPC		0.28
ClinPred		0.37	T
GERP RS		1.6
Varity_R		0.065
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs4687657; hg19: chr3-52852538;