10-7576593-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_030569.7(ITIH5):c.1838G>A(p.Arg613His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,028 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (15 hom.)
• Consequence: ITIH5 NM_030569.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010210663).
• BP6: Variant 10-7576593-C-T is Benign according to our data. Variant chr10-7576593-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 708947.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH5	NM_030569.7	c.1838G>A	p.Arg613His	missense_variant	10/14	ENST00000397146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH5	ENST00000397146.7	c.1838G>A	p.Arg613His	missense_variant	10/14	1	NM_030569.7	P1

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00252 AC: 633 AN: 250880 Hom.: 2 AF XY: 0.00281 AC XY: 382 AN XY: 135730

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00343

Gnomad FIN exome AF: 0.00243

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00250 AC: 3657 AN: 1461668 Hom.: 15 Cov.: 69 AF XY: 0.00249 AC XY: 1814 AN XY: 727156

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00298

Gnomad4 FIN exome AF: 0.00192

Gnomad4 NFE exome AF: 0.00260

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.00213 AC XY: 159 AN XY: 74514

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00228

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00415

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.6
Dann	Benign	0.47
DEOGEN2	Benign	0.0032	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	1.8	N;.;N
REVEL	Benign	0.061
Sift	Benign	0.75	T;.;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.055
MVP		0.055
ClinPred		0.00067	T
GERP RS		-2.1
gMVP		0.38

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: rs148811531; hg19: chr10-7618556; COSMIC: COSV53662819; COSMIC: COSV53662819;