3-52786965-A-C

Variant names:

• chr3-52786965-A-C
• rs678
• NM_002215.4:c.1754A>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E585V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITIH1 NM_002215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05
• Publications: 60 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002215.4. 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
	ITIH1	NM_002215.4	MANE Select	c.1754A>C	p.Glu585Ala	missense	Exon 14 of 22	NP_002206.2	P19827-1
	ITIH1	NM_001166434.3		c.1328A>C	p.Glu443Ala	missense	Exon 12 of 20	NP_001159906.1	P19827-2
	ITIH1	NM_001166435.2		c.890A>C	p.Glu297Ala	missense	Exon 10 of 18	NP_001159907.1	P19827-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH1	ENST00000273283.7	TSL:1 MANE Select	c.1754A>C	p.Glu585Ala	missense	Exon 14 of 22	ENSP00000273283.2	P19827-1
	ITIH1	ENST00000943717.1		c.1754A>C	p.Glu585Ala	missense	Exon 14 of 22	ENSP00000613776.1
	ITIH1	ENST00000943715.1		c.1754A>C	p.Glu585Ala	missense	Exon 14 of 22	ENSP00000613774.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.1
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.14	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
Mutation Taster		=29/71	disease causing

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: rs678; hg19: chr3-52820981;