rs147753898

Variant names:

• chr3-52814278-G-A
• rs147753898
• NM_002218.5:c.2557C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52814278-G-A
• chr3-52814278-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002218.5(ITIH4):​c.2557C>T​(p.Arg853Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ITIH4 NM_002218.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16827044).

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.2557C>T	p.Arg853Cys	missense	Exon 22 of 24	NP_002209.2
	ITIH4	NM_001166449.2		c.2467C>T	p.Arg823Cys	missense	Exon 20 of 22	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.2557C>T	p.Arg853Cys	missense	Exon 22 of 24	ENSP00000266041.4	Q14624-1
	ITIH4	ENST00000485816.5	TSL:1	c.2572C>T	p.Arg858Cys	missense	Exon 22 of 24	ENSP00000417824.1	B7ZKJ8
	ITIH4	ENST00000441637.2	TSL:1	c.1921C>T	p.Arg641Cys	missense	Exon 16 of 18	ENSP00000395634.2	H7C0L5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250940 AF XY: 0.00000737

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461704 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74446

African (AFR) AF: 0.0000481 AC: 2 AN: 41554

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.020
Eigen_PC	Benign	-0.021
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.025	D
Polyphen		0.97	D
Vest4		0.35
MVP		0.52
MPC		0.95
ClinPred		0.22	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.30
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs147753898; hg19: chr3-52848294; COSMIC: COSV56578241; COSMIC: COSV56578241;