10-7569715-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_030569.7(ITIH5):c.2102G>C(p.Gly701Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,612,878 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00079 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (2 hom.)
• Consequence: ITIH5 NM_030569.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33211228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH5	NM_030569.7	c.2102G>C	p.Gly701Ala	missense_variant	12/14	ENST00000397146.7
ITIH5	NM_032817.6	c.1460G>C	p.Gly487Ala	missense_variant	8/10
ITIH5	XM_011519713.4	c.2177G>C	p.Gly726Ala	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH5	ENST00000397146.7	c.2102G>C	p.Gly701Ala	missense_variant	12/14	1	NM_030569.7	P1
ITIH5	ENST00000613909.4	c.1460G>C	p.Gly487Ala	missense_variant	8/10	1
ITIH5	ENST00000473591.1	n.364G>C		non_coding_transcript_exon_variant	2/3	3
ITIH5	ENST00000492668.5	n.269G>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.000789 AC: 120 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000656 AC: 164 AN: 250162 Hom.: 1 AF XY: 0.000747 AC XY: 101 AN XY: 135224

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000461

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000958 AC: 1400 AN: 1460720 Hom.: 2 Cov.: 30 AF XY: 0.000918 AC XY: 667 AN XY: 726698

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000427

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000454

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000789 AC: 120 AN: 152158 Hom.: 1 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74340

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.000854

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000601 AC: 73

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.2102G>C (p.G701A) alteration is located in exon 12 (coding exon 12) of the ITIH5 gene. This alteration results from a G to C substitution at nucleotide position 2102, causing the glycine (G) at amino acid position 701 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.074	T;T
Vest4		0.75
MVP		0.58
ClinPred		0.24	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.79

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: rs139418789; hg19: chr10-7611678;