10-7563162-C-T

Variant names:

• chr10-7563162-C-T
• rs781142532
• NM_030569.7:c.2750G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_030569.7(ITIH5):​c.2750G>A​(p.Gly917Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G917A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ITIH5 NM_030569.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46
• Publications: 1 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

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.2750G>A	p.Gly917Glu	missense	Exon 14 of 14	NP_085046.5
	ITIH5	NM_032817.6		c.2108G>A	p.Gly703Glu	missense	Exon 10 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.2750G>A	p.Gly917Glu	missense	Exon 14 of 14	ENSP00000380333.3	C9J2H1
	ITIH5	ENST00000613909.4	TSL:1	c.2108G>A	p.Gly703Glu	missense	Exon 10 of 10	ENSP00000485414.1	A0A096LP62
	ITIH5	ENST00000884049.1		c.2825G>A	p.Gly942Glu	missense	Exon 15 of 15	ENSP00000554108.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461832 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.1	T
PhyloP100		7.5
PrimateAI	Uncertain	0.59	T
Sift4G	Pathogenic	0.0	D
Vest4		0.78
MutPred		0.62		Gain of solvent accessibility (P = 0.005)
MVP		0.48
ClinPred		0.99	D
GERP RS		5.8
gMVP		0.92
Mutation Taster		=15/85	disease causing

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: rs781142532; hg19: chr10-7605125;