Genetic Variant NM_002218.5:c.932A>G (chr3-52824510-T-C) – 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.932A>G(p.Asn311Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. N311T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITIH4
NM_002218.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.913

Publications

2 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:

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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 (MetaRNN=0.41075093).

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.932A>G	p.Asn311Ser	missense	Exon 8 of 24	NP_002209.2
ITIH4	NM_001166449.2		c.932A>G	p.Asn311Ser	missense	Exon 8 of 22	NP_001159921.1	Q14624-3
ITIH4-AS1	NR_046615.1		n.285+173T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITIH4	ENST00000266041.9	TSL:1 MANE Select	c.932A>G	p.Asn311Ser	missense	Exon 8 of 24	ENSP00000266041.4	Q14624-1
ITIH4	ENST00000485816.5	TSL:1	c.932A>G	p.Asn311Ser	missense	Exon 8 of 24	ENSP00000417824.1	B7ZKJ8
ITIH4	ENST00000441637.2	TSL:1	c.503A>G	p.Asn168Ser	missense	Exon 5 of 18	ENSP00000395634.2	H7C0L5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.69

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.8

PhyloP100

0.91

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.26

Sift

Benign

0.042

Sift4G

Benign

0.072

Polyphen

0.53

Vest4

0.36

MutPred

0.64

Loss of sheet (P = 0.1158)

MVP

0.77

MPC

0.83

ClinPred

0.67

GERP RS

2.6

Varity_R

0.15

gMVP

0.43

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over