rs1302526349

Variant names:

• chrX-54751011-C-T
• rs1302526349
• NM_198510.3:c.3722G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_198510.3(ITIH6):​c.3722G>A​(p.Gly1241Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000574 in 1,044,999 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000057 (0 hom. 3 hem.)
• Consequence: ITIH6 NM_198510.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28
• Publications: 0 publications found

Genes affected

ITIH6 (HGNC:28907): (inter-alpha-trypsin inhibitor heavy chain family member 6) The protein encoded by this gene belongs to the interalpha trypsin inhibitor heavy chain (ITIH) family. Interalpha trypsin inhibitor (ITI) is composed of two heavy chains (containing VWA domain) and one light chain. The light chain confers the protease-inhibitor function, while the heavy chains are involved in mediating protein-protein interactions with the components of the extracellular matrix. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198510.3. 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
	ITIH6	NM_198510.3	MANE Select	c.3722G>A	p.Gly1241Asp	missense	Exon 12 of 13	NP_940912.1	Q6UXX5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH6	ENST00000218436.7	TSL:1 MANE Select	c.3722G>A	p.Gly1241Asp	missense	Exon 12 of 13	ENSP00000218436.6	Q6UXX5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00 AC: 0 AN: 106164 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000574 AC: 6 AN: 1044999 Hom.: 0 Cov.: 31 AF XY: 0.00000897 AC XY: 3 AN XY: 334389

African (AFR) AF: 0.00 AC: 0 AN: 25327

American (AMR) AF: 0.00 AC: 0 AN: 26988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17319

East Asian (EAS) AF: 0.00 AC: 0 AN: 28169

South Asian (SAS) AF: 0.00 AC: 0 AN: 47347

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37475

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3989

European-Non Finnish (NFE) AF: 0.00000737 AC: 6 AN: 814457

Other (OTH) AF: 0.00 AC: 0 AN: 43928

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.96		Gain of helix (P = 0.0854)
MVP		0.28
MPC		0.047
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.78
gMVP		0.92
Mutation Taster		=82/18	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: rs1302526349; hg19: chrX-54777444;