X-54751011-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH6	NM_198510.3	c.3722G>A	p.Gly1241Asp	missense_variant	Exon 12 of 13	ENST00000218436.7	NP_940912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH6	ENST00000218436.7	c.3722G>A	p.Gly1241Asp	missense_variant	Exon 12 of 13	1	NM_198510.3	ENSP00000218436.6

Frequencies

GnomAD3 genomes Cov.: 23

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000737

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3722G>A (p.G1241D) alteration is located in exon 12 (coding exon 12) of the ITIH6 gene. This alteration results from a G to A substitution at nucleotide position 3722, causing the glycine (G) at amino acid position 1241 to be replaced by an aspartic acid (D). 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	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
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

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: rs1302526349; hg19: chrX-54777444;