10-7566372-C-G

Variant names:

• chr10-7566372-C-G
• rs763259102
• NM_030569.7:c.2185G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030569.7(ITIH5):​c.2185G>C​(p.Ala729Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A729T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ITIH5 NM_030569.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.56
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41492727).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030569.7. 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
	ITIH5	NM_030569.7	MANE Select	c.2185G>C	p.Ala729Pro	missense	Exon 13 of 14	NP_085046.5
	ITIH5	NM_032817.6		c.1543G>C	p.Ala515Pro	missense	Exon 9 of 10	NP_116206.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH5	ENST00000397146.7	TSL:1 MANE Select	c.2185G>C	p.Ala729Pro	missense	Exon 13 of 14	ENSP00000380333.3	C9J2H1
	ITIH5	ENST00000613909.4	TSL:1	c.1543G>C	p.Ala515Pro	missense	Exon 9 of 10	ENSP00000485414.1	A0A096LP62
	ITIH5	ENST00000884049.1		c.2260G>C	p.Ala754Pro	missense	Exon 14 of 15	ENSP00000554108.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448452 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717974

African (AFR) AF: 0.00 AC: 0 AN: 33232

American (AMR) AF: 0.00 AC: 0 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39332

South Asian (SAS) AF: 0.00 AC: 0 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100658

Other (OTH) AF: 0.00 AC: 0 AN: 59792

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0055	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0090	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.2	T
PhyloP100		4.6
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.28	T
Vest4		0.45
MutPred		0.61		Gain of glycosylation at A729 (P = 0.0029)
MVP		0.48
ClinPred		0.99	D
GERP RS		5.8
gMVP		0.67
Mutation Taster		=62/38	polymorphism

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: rs763259102; hg19: chr10-7608335;