3-52821213-T-C

Variant names:

• chr3-52821213-T-C
• rs2239547
• NM_002218.5:c.1540-83A>G

Variant summary

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

The NM_002218.5(ITIH4):​c.1540-83A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,517,096 control chromosomes in the GnomAD database, including 56,135 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 0.27 (5891 hom., cov: 31)
  • Exomes 𝑓: 0.26 (50244 hom.)
• Consequence: ITIH4 NM_002218.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0800
• Publications: 56 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.394 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.1540-83A>G		intron	N/A	NP_002209.2
	ITIH4	NM_001166449.2		c.1540-83A>G		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.1540-83A>G		intron	N/A	ENSP00000266041.4	Q14624-1
	ITIH4	ENST00000485816.5	TSL:1	c.1540-83A>G		intron	N/A	ENSP00000417824.1	B7ZKJ8
	ITIH4	ENST00000441637.2	TSL:1	c.1111-83A>G		intron	N/A	ENSP00000395634.2	H7C0L5

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40977 AN: 151704 Hom.: 5893 Cov.: 31

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.264 AC: 360738 AN: 1365276 Hom.: 50244 AF XY: 0.260 AC XY: 175414 AN XY: 675478

African (AFR) AF: 0.206 AC: 6480 AN: 31414

American (AMR) AF: 0.477 AC: 18802 AN: 39392

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 7438 AN: 22462

East Asian (EAS) AF: 0.348 AC: 13570 AN: 38992

South Asian (SAS) AF: 0.129 AC: 9844 AN: 76520

European-Finnish (FIN) AF: 0.275 AC: 11388 AN: 41436

Middle Eastern (MID) AF: 0.276 AC: 1065 AN: 3852

European-Non Finnish (NFE) AF: 0.263 AC: 277683 AN: 1054570

Other (OTH) AF: 0.255 AC: 14468 AN: 56638

GnomAD4 genome AF: 0.270 AC: 40998 AN: 151820 Hom.: 5891 Cov.: 31 AF XY: 0.271 AC XY: 20106 AN XY: 74198

African (AFR) AF: 0.214 AC: 8881 AN: 41406

American (AMR) AF: 0.402 AC: 6145 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1137 AN: 3470

East Asian (EAS) AF: 0.320 AC: 1641 AN: 5126

South Asian (SAS) AF: 0.139 AC: 666 AN: 4808

European-Finnish (FIN) AF: 0.278 AC: 2929 AN: 10530

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18530 AN: 67894

Other (OTH) AF: 0.278 AC: 585 AN: 2108

Alfa AF: 0.272 Hom.: 11920

Bravo AF: 0.280

Asia WGS AF: 0.247 AC: 858 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.67
PhyloP100		-0.080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2239547; hg19: chr3-52855229; COSMIC: COSV56573580; COSMIC: COSV56573580;