rs4687554

Positions:

• chr3-52830119-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.90+434A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 346,970 control chromosomes in the GnomAD database, including 10,272 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 0.25 (4863 hom., cov: 34)
  • Exomes 𝑓: 0.22 (5409 hom.)
• Consequence: ITIH4 NM_002218.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH4	NM_002218.5	c.90+434A>G		intron_variant		ENST00000266041.9
ITIH4	NM_001166449.2	c.90+434A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH4	ENST00000266041.9	c.90+434A>G		intron_variant		1	NM_002218.5	P2

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37354 AN: 152102 Hom.: 4862 Cov.: 34

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.221 AC: 43083 AN: 194750 Hom.: 5409 Cov.: 0 AF XY: 0.207 AC XY: 22062 AN XY: 106616

Gnomad4 AFR exome AF: 0.213

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.246 AC: 37379 AN: 152220 Hom.: 4863 Cov.: 34 AF XY: 0.247 AC XY: 18422 AN XY: 74434

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.246

Alfa AF: 0.233 Hom.: 2081

Bravo AF: 0.256

Asia WGS AF: 0.237 AC: 823 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.7
DANN	Benign	0.44

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: rs4687554; hg19: chr3-52864135;