3-52824417-G-A

Variant names:

• chr3-52824417-G-A
• rs143388513
• NM_002218.5:c.1025C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002218.5(ITIH4):​c.1025C>T​(p.Ala342Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: ITIH4 NM_002218.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.843

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06372926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH4	NM_002218.5	c.1025C>T	p.Ala342Val	missense_variant	Exon 8 of 24	ENST00000266041.9	NP_002209.2
ITIH4	NM_001166449.2	c.1025C>T	p.Ala342Val	missense_variant	Exon 8 of 22		NP_001159921.1
ITIH4-AS1	NR_046615.1	n.285+80G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH4	ENST00000266041.9	c.1025C>T	p.Ala342Val	missense_variant	Exon 8 of 24	1	NM_002218.5	ENSP00000266041.4
ENSG00000243696	ENST00000468472.1	n.*1157C>T		non_coding_transcript_exon_variant	Exon 13 of 24	2		ENSP00000422253.1
ENSG00000243696	ENST00000468472.1	n.*1157C>T		3_prime_UTR_variant	Exon 13 of 24	2		ENSP00000422253.1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000366 AC: 92 AN: 251316 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135844

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000331 AC: 484 AN: 1461824 Hom.: 1 Cov.: 32 AF XY: 0.000301 AC XY: 219 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000365

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74472

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000404 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1025C>T (p.A342V) alteration is located in exon 8 (coding exon 8) of the ITIH4 gene. This alteration results from a C to T substitution at nucleotide position 1025, causing the alanine (A) at amino acid position 342 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.9
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.81	P;P;.
Vest4		0.15
MVP		0.73
MPC		0.63
ClinPred		0.040	T
GERP RS		-3.0
Varity_R		0.046
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs143388513; hg19: chr3-52858433;