chr3-52796586-G-A

Position:

• chr3-52796586-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002217.4(ITIH3):​c.220G>A​(p.Ala74Thr) 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 1,461,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITIH3 NM_002217.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28925937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH3	NM_002217.4	c.220G>A	p.Ala74Thr	missense_variant	3/22	ENST00000449956.3	NP_002208.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH3	ENST00000449956.3	c.220G>A	p.Ala74Thr	missense_variant	3/22	1	NM_002217.4	ENSP00000415769.2
ITIH3	ENST00000703834.1	c.220G>A	p.Ala74Thr	missense_variant	3/23			ENSP00000515492.1
ITIH3	ENST00000416872.6	c.220G>A	p.Ala74Thr	missense_variant	3/17	2		ENSP00000413922.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461010 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.220G>A (p.A74T) alteration is located in exon 3 (coding exon 3) of the ITIH3 gene. This alteration results from a G to A substitution at nucleotide position 220, causing the alanine (A) at amino acid position 74 to be replaced by a threonine (T). 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	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	.;.;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	.;N;N
REVEL	Benign	0.087
Sift	Benign	0.051	.;T;D
Sift4G	Uncertain	0.029	D;D;T
Polyphen		0.90, 0.95	.;P;P
Vest4		0.17
MutPred		0.54		Gain of phosphorylation at A74 (P = 0.0794);Gain of phosphorylation at A74 (P = 0.0794);Gain of phosphorylation at A74 (P = 0.0794);
MVP		0.35
MPC		0.47
ClinPred		0.79	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52830602;