rs2275069

Variant names:

• chr10-7576723-T-G
• rs2275069
• NM_030569.7:c.1708A>C

Variant summary

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

The ENST00000397146.7(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. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (20260 hom., cov: 32)
  • Exomes 𝑓: 0.55 (219710 hom.)
• Consequence: ITIH5 ENST00000397146.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115
• Publications: 33 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397146.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH5	NM_030569.7	MANE Select	c.1708A>C	p.Thr570Pro	missense	Exon 10 of 14	NP_085046.5
	ITIH5	NM_032817.6		c.1066A>C	p.Thr356Pro	missense	Exon 6 of 10	NP_116206.4
	ITIH5	NM_001001851.3		c.1708A>C	p.Thr570Pro	missense	Exon 10 of 12	NP_001001851.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH5	ENST00000397146.7	TSL:1 MANE Select	c.1708A>C	p.Thr570Pro	missense	Exon 10 of 14	ENSP00000380333.3
	ITIH5	ENST00000613909.4	TSL:1	c.1066A>C	p.Thr356Pro	missense	Exon 6 of 10	ENSP00000485414.1
	ITIH5	ENST00000397145.6	TSL:2	c.1708A>C	p.Thr570Pro	missense	Exon 10 of 12	ENSP00000380332.2

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

GnomAD2 exomes AF: 0.550 AC: 138172 AN: 251014 AF XY: 0.550

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 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

African (AFR) AF: 0.405 AC: 13562 AN: 33480

American (AMR) AF: 0.544 AC: 24318 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 13142 AN: 26134

East Asian (EAS) AF: 0.770 AC: 30555 AN: 39700

South Asian (SAS) AF: 0.530 AC: 45674 AN: 86256

European-Finnish (FIN) AF: 0.592 AC: 31574 AN: 53358

Middle Eastern (MID) AF: 0.435 AC: 2509 AN: 5768

European-Non Finnish (NFE) AF: 0.544 AC: 604344 AN: 1111946

Other (OTH) AF: 0.534 AC: 32277 AN: 60390

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

African (AFR) AF: 0.408 AC: 16904 AN: 41458

American (AMR) AF: 0.525 AC: 8019 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1726 AN: 3472

East Asian (EAS) AF: 0.773 AC: 3977 AN: 5144

South Asian (SAS) AF: 0.546 AC: 2631 AN: 4818

European-Finnish (FIN) AF: 0.594 AC: 6284 AN: 10586

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.537 AC: 36481 AN: 67930

Other (OTH) AF: 0.492 AC: 1040 AN: 2112

Alfa AF: 0.528 Hom.: 52371

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 v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.015	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.12
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.029
Sift	Benign	1.0	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.019
ClinPred		0.0018	T
GERP RS		1.3
gMVP		0.58
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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