rs2275069

Positions:

• chr10-7576723-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030569.7(ITIH5):​c.1708A>C​(p.Thr570Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,613,736 control chromosomes in the GnomAD database, including 239,970 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (20260 hom., cov: 32)
  • Exomes 𝑓: 0.55 (219710 hom.)
• Consequence: ITIH5 NM_030569.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115

Genes affected

ITIH5 (HGNC:21449): (inter-alpha-trypsin inhibitor heavy chain 5) This gene encodes a heavy chain component of one of the inter-alpha-trypsin inhibitor (ITI) family members. ITI proteins are involved in extracellular matrix stabilization and in the prevention of tumor metastasis. They are also structurally related plasma serine protease inhibitors and are composed of a light chain and varying numbers of heavy chains. This family member is thought to function as a tumor suppressor in breast and thyroid cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5562256E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH5	NM_030569.7	c.1708A>C	p.Thr570Pro	missense_variant	10/14	ENST00000397146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH5	ENST00000397146.7	c.1708A>C	p.Thr570Pro	missense_variant	10/14	1	NM_030569.7	P1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77518 AN: 151892 Hom.: 20251 Cov.: 32

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.493

GnomAD3 exomes AF: 0.550 AC: 138172 AN: 251014 Hom.: 38805 AF XY: 0.550 AC XY: 74599 AN XY: 135678

Gnomad AFR exome AF: 0.400

Gnomad AMR exome AF: 0.547

Gnomad ASJ exome AF: 0.503

Gnomad EAS exome AF: 0.783

Gnomad SAS exome AF: 0.529

Gnomad FIN exome AF: 0.591

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.546 AC: 797955 AN: 1461726 Hom.: 219710 Cov.: 67 AF XY: 0.545 AC XY: 396037 AN XY: 727158

Gnomad4 AFR exome AF: 0.405

Gnomad4 AMR exome AF: 0.544

Gnomad4 ASJ exome AF: 0.503

Gnomad4 EAS exome AF: 0.770

Gnomad4 SAS exome AF: 0.530

Gnomad4 FIN exome AF: 0.592

Gnomad4 NFE exome AF: 0.544

Gnomad4 OTH exome AF: 0.534

GnomAD4 genome AF: 0.510 AC: 77565 AN: 152010 Hom.: 20260 Cov.: 32 AF XY: 0.517 AC XY: 38387 AN XY: 74302

Gnomad4 AFR AF: 0.408

Gnomad4 AMR AF: 0.525

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.773

Gnomad4 SAS AF: 0.546

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.492

Alfa AF: 0.533 Hom.: 41289

Bravo AF: 0.504

TwinsUK AF: 0.557 AC: 2065

ALSPAC AF: 0.549 AC: 2115

ESP6500AA AF: 0.407 AC: 1795

ESP6500EA AF: 0.538 AC: 4630

ExAC AF: 0.546 AC: 66248

Asia WGS AF: 0.605 AC: 2106 AN: 3478

EpiCase AF: 0.525

EpiControl AF: 0.524

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.1
DANN	Benign	0.087
DEOGEN2	Benign	0.0026	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.015	T;T;T
MetaRNN	Benign	0.0000016	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.4	N;.;N
REVEL	Benign	0.029
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.019
ClinPred		0.0018	T
GERP RS		1.3
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs2275069; hg19: chr10-7618686; COSMIC: COSV53669275; COSMIC: COSV53669275;