rs2535633

Variant names:

• chr3-52825614-C-G
• rs2535633
• NM_002218.5:c.759+272G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002218.5(ITIH4):​c.759+272G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 151,930 control chromosomes in the GnomAD database, including 18,644 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (18644 hom., cov: 32)
• Consequence: ITIH4 NM_002218.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.285
• Publications: 30 publications found

Genes affected

ITIH4 (HGNC:6169): (inter-alpha-trypsin inhibitor heavy chain 4) The protein encoded by this gene is secreted into the blood, where it is cleaved by plasma kallikrein into two smaller forms. Expression of this gene has been detected only in liver, and it seems to be upregulated during surgical trauma. This gene is part of a cluster of similar genes on chromosome 3. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ENSG00000243696 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002218.5. 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
	ITIH4	NM_002218.5	MANE Select	c.759+272G>C		intron	N/A	NP_002209.2
	ITIH4	NM_001166449.2		c.759+272G>C		intron	N/A	NP_001159921.1	Q14624-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH4	ENST00000266041.9	TSL:1 MANE Select	c.759+272G>C		intron	N/A	ENSP00000266041.4	Q14624-1
	ITIH4	ENST00000485816.5	TSL:1	c.759+272G>C		intron	N/A	ENSP00000417824.1	B7ZKJ8
	ITIH4	ENST00000441637.2	TSL:1	c.330+272G>C		intron	N/A	ENSP00000395634.2	H7C0L5

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72747 AN: 151812 Hom.: 18621 Cov.: 32

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.453

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.479 AC: 72822 AN: 151930 Hom.: 18644 Cov.: 32 AF XY: 0.477 AC XY: 35446 AN XY: 74266

African (AFR) AF: 0.663 AC: 27456 AN: 41416

American (AMR) AF: 0.543 AC: 8289 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1537 AN: 3470

East Asian (EAS) AF: 0.382 AC: 1972 AN: 5160

South Asian (SAS) AF: 0.398 AC: 1921 AN: 4824

European-Finnish (FIN) AF: 0.353 AC: 3721 AN: 10532

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.388 AC: 26367 AN: 67942

Other (OTH) AF: 0.454 AC: 957 AN: 2106

Alfa AF: 0.447 Hom.: 2002

Bravo AF: 0.503

Asia WGS AF: 0.446 AC: 1548 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.1
DANN	Benign	0.29
PhyloP100		0.28
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: rs2535633; hg19: chr3-52859630;