NM_002217.4:c.208C>A

Variant names:

• chr3-52796574-C-A
• rs1431220365
• NM_002217.4:c.208C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002217.4(ITIH3):​c.208C>A​(p.Arg70Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,166 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. R70C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ITIH3 NM_002217.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.396
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16411969).

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.208C>A	p.Arg70Ser	missense	Exon 3 of 22	NP_002208.3	Q06033-1
	ITIH3	NM_001392019.1		c.208C>A	p.Arg70Ser	missense	Exon 3 of 23	NP_001378948.1	A0A994J439
	ITIH3	NM_001392020.1		c.208C>A	p.Arg70Ser	missense	Exon 3 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.208C>A	p.Arg70Ser	missense	Exon 3 of 22	ENSP00000415769.2	Q06033-1
	ITIH3	ENST00000703834.1		c.208C>A	p.Arg70Ser	missense	Exon 3 of 23	ENSP00000515492.1	A0A994J439
	ITIH3	ENST00000889655.1		c.208C>A	p.Arg70Ser	missense	Exon 3 of 21	ENSP00000559714.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461166 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726808

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111642

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.40
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.057
Sift	Benign	0.29	T
Sift4G	Benign	0.15	T
Polyphen		0.19	B
Vest4		0.34
MutPred		0.51		Loss of MoRF binding (P = 0.0378)
MVP		0.30
MPC		0.14
ClinPred		0.64	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.46
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1431220365; hg19: chr3-52830590; COSMIC: COSV99835148; COSMIC: COSV99835148;