rs3617

chr3-52799789-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002217.4(ITIH3):c.943C>A(p.Gln315Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,612,218 control chromosomes in the GnomAD database, including 179,023 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.53 (22824 hom., cov: 33)
  • Exomes 𝑓: 0.46 (156199 hom.)
• Consequence: ITIH3 NM_002217.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.771

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9009592E-6).
• BP6: Variant 3-52799789-C-A is Benign according to our data. Variant chr3-52799789-C-A is described in ClinVar as [Benign]. Clinvar id is 1279402.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH3	NM_002217.4	c.943C>A	p.Gln315Lys	missense_variant	9/22	ENST00000449956.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH3	ENST00000449956.3	c.943C>A	p.Gln315Lys	missense_variant	9/22	1	NM_002217.4	P1

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81217 AN: 151912 Hom.: 22790 Cov.: 33

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.511

GnomAD3 exomes AF: 0.479 AC: 118451 AN: 247344 Hom.: 29448 AF XY: 0.466 AC XY: 62521 AN XY: 134148

Gnomad AFR exome AF: 0.718

Gnomad AMR exome AF: 0.608

Gnomad ASJ exome AF: 0.486

Gnomad EAS exome AF: 0.408

Gnomad SAS exome AF: 0.346

Gnomad FIN exome AF: 0.440

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.463

GnomAD4 exome AF: 0.459 AC: 669504 AN: 1460190 Hom.: 156199 Cov.: 40 AF XY: 0.454 AC XY: 329916 AN XY: 726328

Gnomad4 AFR exome AF: 0.718

Gnomad4 AMR exome AF: 0.602

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.437

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.456

GnomAD4 genome AF: 0.535 AC: 81309 AN: 152028 Hom.: 22824 Cov.: 33 AF XY: 0.531 AC XY: 39453 AN XY: 74318

Gnomad4 AFR AF: 0.712

Gnomad4 AMR AF: 0.580

Gnomad4 ASJ AF: 0.490

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.513

Alfa AF: 0.474 Hom.: 42033

Bravo AF: 0.557

TwinsUK AF: 0.451 AC: 1671

ALSPAC AF: 0.450 AC: 1733

ESP6500AA AF: 0.710 AC: 2690

ESP6500EA AF: 0.466 AC: 3852

ExAC AF: 0.479 AC: 57829

Asia WGS AF: 0.448 AC: 1555 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2021

This variant is associated with the following publications: (PMID: 32712163) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.7
Dann	Benign	0.46
DEOGEN2	Benign	0.0035	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.018	T;T;T
MetaRNN	Benign	0.0000019	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.97	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.043
MPC		0.13
ClinPred		0.0051	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.34

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

Other links and lift over

dbSNP: rs3617; hg19: chr3-52833805; COSMIC: COSV69648851; COSMIC: COSV69648851;