Genetic Variant ITIH4:p.Arg409Arg (chr3-52823951-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002218.5(ITIH4):c.1225C>A(p.Arg409Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000438 in 1,597,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

ITIH4
NM_002218.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.73

Publications

0 publications found

Variant links:

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]

ITIH4 links:

ENSG00000243696 (HGNC:):

ENSG00000243696 links:

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

ITIH4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (REVEL=0.208).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITIH4	NM_002218.5	MANE Select	c.1225C>A	p.Arg409Arg	synonymous	Exon 10 of 24	NP_002209.2
ITIH4	NM_001166449.2		c.1225C>A	p.Arg409Arg	synonymous	Exon 10 of 22	NP_001159921.1	Q14624-3
ITIH4-AS1	NR_046615.1		n.17G>T		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITIH4	ENST00000266041.9	TSL:1 MANE Select	c.1225C>A	p.Arg409Arg	synonymous	Exon 10 of 24	ENSP00000266041.4	Q14624-1
ITIH4	ENST00000485816.5	TSL:1	c.1225C>A	p.Arg409Arg	synonymous	Exon 10 of 24	ENSP00000417824.1	B7ZKJ8
ITIH4	ENST00000441637.2	TSL:1	c.796C>A	p.Arg266Arg	synonymous	Exon 7 of 18	ENSP00000395634.2	H7C0L5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000415

AC:

AN:

1445428

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

717876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33034

American (AMR)

AF:

0.00

AC:

AN:

42712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24630

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

82766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00000453

AC:

AN:

1104746

Other (OTH)

AF:

0.0000168

AC:

AN:

59654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.1

(source)

DANN

Benign

0.72

PhyloP100

3.7

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over