rs3617

Variant names:

• chr3-52799789-C-A
• rs3617
• NM_002217.4:c.943C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-52799789-C-A
• chr3-52799789-C-G
• chr3-52799789-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q315R) has been classified as Uncertain significance.

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.771
• Publications: 67 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 1279402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002217.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH3	NM_002217.4	MANE Select	c.943C>A	p.Gln315Lys	missense	Exon 9 of 22	NP_002208.3	Q06033-1
	ITIH3	NM_001392019.1		c.943C>A	p.Gln315Lys	missense	Exon 9 of 23	NP_001378948.1	A0A994J439
	ITIH3	NM_001392020.1		c.943C>A	p.Gln315Lys	missense	Exon 9 of 22	NP_001378949.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH3	ENST00000449956.3	TSL:1 MANE Select	c.943C>A	p.Gln315Lys	missense	Exon 9 of 22	ENSP00000415769.2	Q06033-1
	ITIH3	ENST00000703834.1		c.943C>A	p.Gln315Lys	missense	Exon 9 of 23	ENSP00000515492.1	A0A994J439
	ITIH3	ENST00000889655.1		c.943C>A	p.Gln315Lys	missense	Exon 9 of 21	ENSP00000559714.1

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

GnomAD2 exomes AF: 0.479 AC: 118451 AN: 247344 AF XY: 0.466

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 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

African (AFR) AF: 0.718 AC: 24016 AN: 33452

American (AMR) AF: 0.602 AC: 26827 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12928 AN: 26118

East Asian (EAS) AF: 0.458 AC: 18164 AN: 39684

South Asian (SAS) AF: 0.344 AC: 29659 AN: 86154

European-Finnish (FIN) AF: 0.437 AC: 23280 AN: 53218

Middle Eastern (MID) AF: 0.456 AC: 2626 AN: 5762

European-Non Finnish (NFE) AF: 0.454 AC: 504475 AN: 1110904

Other (OTH) AF: 0.456 AC: 27529 AN: 60322

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

African (AFR) AF: 0.712 AC: 29507 AN: 41454

American (AMR) AF: 0.580 AC: 8854 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1700 AN: 3470

East Asian (EAS) AF: 0.420 AC: 2170 AN: 5166

South Asian (SAS) AF: 0.351 AC: 1691 AN: 4820

European-Finnish (FIN) AF: 0.424 AC: 4481 AN: 10564

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31195 AN: 67964

Other (OTH) AF: 0.513 AC: 1085 AN: 2114

Alfa AF: 0.484 Hom.: 90462

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.018	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.77
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.18
Sift	Benign	0.43	T
Sift4G	Benign	0.97	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.13
ClinPred		0.0051	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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