NM_002218.5:c.2092C>A

Variant names:

• chr3-52818522-G-T
• rs4687657
• NM_002218.5:c.2092C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002218.5(ITIH4):​c.2092C>A​(p.Pro698Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,601,242 control chromosomes in the GnomAD database, including 58,684 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.27 (5851 hom., cov: 32)
  • Exomes 𝑓: 0.26 (52833 hom.)
• Consequence: ITIH4 NM_002218.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.330
• Publications: 61 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.5569072E-4).
• BP6: Variant 3-52818522-G-T is Benign according to our data. Variant chr3-52818522-G-T is described in ClinVar as Benign. ClinVar VariationId is 3059528.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH4	NM_002218.5	c.2092C>A	p.Pro698Thr	missense_variant	Exon 18 of 24	ENST00000266041.9	NP_002209.2
ITIH4	NM_001166449.2	c.2002C>A	p.Pro668Thr	missense_variant	Exon 16 of 22		NP_001159921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH4	ENST00000266041.9	c.2092C>A	p.Pro698Thr	missense_variant	Exon 18 of 24	1	NM_002218.5	ENSP00000266041.4
ENSG00000243696	ENST00000468472.1	n.*3462C>A		non_coding_transcript_exon_variant	Exon 20 of 24	2		ENSP00000422253.1
ENSG00000243696	ENST00000468472.1	n.*3462C>A		3_prime_UTR_variant	Exon 20 of 24	2		ENSP00000422253.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40896 AN: 151830 Hom.: 5854 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.281 AC: 64561 AN: 229774 AF XY: 0.267

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.300

Gnomad FIN exome AF: 0.286

Gnomad NFE exome AF: 0.260

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.264 AC: 382228 AN: 1449294 Hom.: 52833 Cov.: 34 AF XY: 0.259 AC XY: 186570 AN XY: 719900

African (AFR) AF: 0.205 AC: 6812 AN: 33230

American (AMR) AF: 0.473 AC: 20233 AN: 42734

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8687 AN: 25940

East Asian (EAS) AF: 0.346 AC: 13529 AN: 39154

South Asian (SAS) AF: 0.129 AC: 10846 AN: 84404

European-Finnish (FIN) AF: 0.278 AC: 14653 AN: 52652

Middle Eastern (MID) AF: 0.276 AC: 1587 AN: 5754

European-Non Finnish (NFE) AF: 0.263 AC: 290603 AN: 1105508

Other (OTH) AF: 0.255 AC: 15278 AN: 59918

GnomAD4 genome AF: 0.269 AC: 40909 AN: 151948 Hom.: 5851 Cov.: 32 AF XY: 0.270 AC XY: 20052 AN XY: 74268

African (AFR) AF: 0.212 AC: 8803 AN: 41440

American (AMR) AF: 0.402 AC: 6140 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1135 AN: 3464

East Asian (EAS) AF: 0.317 AC: 1627 AN: 5128

South Asian (SAS) AF: 0.139 AC: 670 AN: 4816

European-Finnish (FIN) AF: 0.280 AC: 2957 AN: 10562

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18507 AN: 67940

Other (OTH) AF: 0.277 AC: 585 AN: 2110

Alfa AF: 0.266 Hom.: 16105

Bravo AF: 0.279

TwinsUK AF: 0.248 AC: 918

ALSPAC AF: 0.260 AC: 1002

ESP6500AA AF: 0.219 AC: 965

ESP6500EA AF: 0.266 AC: 2288

ExAC AF: 0.255 AC: 30789

Asia WGS AF: 0.245 AC: 848 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ITIH4-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.41
DANN	Benign	0.74
DEOGEN2	Benign	0.38	T;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.35	T;T;T
MetaRNN	Benign	0.00036	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L;.;.
PhyloP100		-0.33
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.098
Sift	Uncertain	0.017	D;D;T
Sift4G	Benign	0.15	T;T;D
Polyphen		0.011	B;B;.
Vest4		0.052
MPC		0.31
ClinPred		0.012	T
GERP RS		1.6
Varity_R		0.094
gMVP		0.31
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4687657; hg19: chr3-52852538; COSMIC: COSV56574158; COSMIC: COSV56574158;