chr3-52824417-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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. 15/22 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
• Publications: 2 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:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06372926).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002218.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH4	NM_002218.5	MANE Select	c.1025C>T	p.Ala342Val	missense	Exon 8 of 24	NP_002209.2
	ITIH4	NM_001166449.2		c.1025C>T	p.Ala342Val	missense	Exon 8 of 22	NP_001159921.1	Q14624-3
	ITIH4-AS1	NR_046615.1		n.285+80G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH4	ENST00000266041.9	TSL:1 MANE Select	c.1025C>T	p.Ala342Val	missense	Exon 8 of 24	ENSP00000266041.4	Q14624-1
	ITIH4	ENST00000485816.5	TSL:1	c.1025C>T	p.Ala342Val	missense	Exon 8 of 24	ENSP00000417824.1	B7ZKJ8
	ITIH4	ENST00000441637.2	TSL:1	c.596C>T	p.Ala199Val	missense	Exon 5 of 18	ENSP00000395634.2	H7C0L5

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

GnomAD2 exomes AF: 0.000366 AC: 92 AN: 251316 AF XY: 0.000383

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 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

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000805 AC: 36 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000365 AC: 406 AN: 1111998

Other (OTH) AF: 0.000431 AC: 26 AN: 60394

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

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000427 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.84
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.25
Sift	Benign	0.19	T
Sift4G	Benign	0.26	T
Polyphen		0.81	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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs143388513; hg19: chr3-52858433;