rs2239547

Positions:

• chr3-52821213-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH4	NM_002218.5	c.1540-83A>G		intron_variant		ENST00000266041.9
ITIH4	NM_001166449.2	c.1540-83A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH4	ENST00000266041.9	c.1540-83A>G		intron_variant		1	NM_002218.5	P2

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

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.477

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.348

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.263

Gnomad4 OTH exome AF: 0.255

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

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.320

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.278

Alfa AF: 0.276 Hom.: 6040

Bravo AF: 0.280

Asia WGS AF: 0.247 AC: 858 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2239547; hg19: chr3-52855229; COSMIC: COSV56573580; COSMIC: COSV56573580;