Variant 3-52797923-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002217.4(ITIH3):c.656G>C(p.Gly219Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,436,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ITIH3
NM_002217.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

Variant links:

Genes affected

ITIH3 (HGNC:6168): (inter-alpha-trypsin inhibitor heavy chain 3) This gene encodes the heavy chain subunit of the pre-alpha-trypsin inhibitor complex. This complex may stabilize the extracellular matrix through its ability to bind hyaluronic acid. Polymorphisms of this gene may be associated with increased risk for schizophrenia and major depressive disorder. This gene is present in an inter-alpha-trypsin inhibitor family gene cluster on chromosome 3. [provided by RefSeq, Jul 2015]

ITIH3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2523061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH3	NM_002217.4 linkuse as main transcript	c.656G>C	p.Gly219Ala	missense_variant	6/22	ENST00000449956.3	NP_002208.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH3	ENST00000449956.3 linkuse as main transcript	c.656G>C	p.Gly219Ala	missense_variant	6/22	1	NM_002217.4	ENSP00000415769	P1	Q06033-1
ITIH3	ENST00000703834.1 linkuse as main transcript	c.656G>C	p.Gly219Ala	missense_variant	6/23			ENSP00000515492
ITIH3	ENST00000416872.6 linkuse as main transcript	c.656G>C	p.Gly219Ala	missense_variant	6/17	2		ENSP00000413922

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1436568

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

712974

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000364

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2023

The c.656G>C (p.G219A) alteration is located in exon 6 (coding exon 6) of the ITIH3 gene. This alteration results from a G to C substitution at nucleotide position 656, causing the glycine (G) at amino acid position 219 to be replaced by an alanine (A). 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

0.21

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

T;.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

D;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.4

.;.;L

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.5

.;N;N

REVEL

Benign

0.10

Sift

Benign

0.35

.;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

1.0, 1.0

.;D;D

Vest4

0.42

MutPred

0.23

Loss of stability (P = 0.0451);Loss of stability (P = 0.0451);Loss of stability (P = 0.0451);

MVP

0.39

MPC

0.12

ClinPred

0.85

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over