rs678

Positions:

• chr3-52786965-A-C
• chr3-52786965-A-G
• chr3-52786965-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002215.4(ITIH1):​c.1754A>C​(p.Glu585Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITIH1 NM_002215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05

Genes affected

ITIH1 (HGNC:6166): (inter-alpha-trypsin inhibitor heavy chain 1) This gene encodes a member of the inter-alpha-trypsin inhibitor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the heavy chain of the inter-alpha-trypsin inhibitor complex, which is secreted by hepatocytes into the blood. The heavy chain also interacts with hyaluronan, and this interaction may play a role in ovulation and fertilization, and has been implicated in multiple inflammatory diseases. This gene is present in a gene cluster on chromosome 3. [provided by RefSeq, Nov 2015]

ITIH1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH1	NM_002215.4	c.1754A>C	p.Glu585Ala	missense_variant	14/22	ENST00000273283.7	NP_002206.2
ITIH1	NM_001166434.3	c.1328A>C	p.Glu443Ala	missense_variant	12/20		NP_001159906.1
ITIH1	NM_001166435.2	c.890A>C	p.Glu297Ala	missense_variant	10/18		NP_001159907.1
ITIH1	NM_001166436.2	c.890A>C	p.Glu297Ala	missense_variant	10/18		NP_001159908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH1	ENST00000273283.7	c.1754A>C	p.Glu585Ala	missense_variant	14/22	1	NM_002215.4	ENSP00000273283.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D;D;N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.35
MutPred		0.27		Gain of MoRF binding (P = 0.0168);.;.;
MVP		0.68
MPC		0.67
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.55
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs678; hg19: chr3-52820981;