X-54750046-C-T

Variant names:

• chrX-54750046-C-T
• rs143515399
• NM_198510.3:c.3791G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_198510.3(ITIH6):​c.3791G>A​(p.Arg1264Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,209,781 control chromosomes in the GnomAD database, including 5 homozygotes. There are 258 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., 148 hem., cov: 22)
  • Exomes 𝑓: 0.00039 (2 hom. 110 hem.)
• Consequence: ITIH6 NM_198510.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.08
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041105747).
• BP6: Variant X-54750046-C-T is Benign according to our data. Variant chrX-54750046-C-T is described in ClinVar as Benign. ClinVar VariationId is 3040095.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 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.3791G>A	p.Arg1264Lys	missense	Exon 13 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.3791G>A	p.Arg1264Lys	missense	Exon 13 of 13	ENSP00000218436.6	Q6UXX5

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 473 AN: 111820 Hom.: 3 Cov.: 22

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00265

GnomAD2 exomes AF: 0.00113 AC: 207 AN: 182649 AF XY: 0.000819

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.000658

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: 0.000888

GnomAD4 exome AF: 0.000393 AC: 432 AN: 1097906 Hom.: 2 Cov.: 30 AF XY: 0.000303 AC XY: 110 AN XY: 363282

African (AFR) AF: 0.0134 AC: 355 AN: 26396

American (AMR) AF: 0.000824 AC: 29 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.000980 AC: 4 AN: 4083

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841953

Other (OTH) AF: 0.000846 AC: 39 AN: 46082

GnomAD4 genome AF: 0.00423 AC: 473 AN: 111875 Hom.: 3 Cov.: 22 AF XY: 0.00435 AC XY: 148 AN XY: 34051

African (AFR) AF: 0.0148 AC: 456 AN: 30835

American (AMR) AF: 0.00113 AC: 12 AN: 10573

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3522

South Asian (SAS) AF: 0.00 AC: 0 AN: 2584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53128

Other (OTH) AF: 0.00262 AC: 4 AN: 1529

Alfa AF: 0.00158 Hom.: 71

Bravo AF: 0.00506

ESP6500AA AF: 0.0120 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ITIH6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.0
DANN	Benign	0.68
DEOGEN2	Benign	0.00059	T
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.020	N
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.083
Sift	Benign	0.83	T
Sift4G	Benign	0.61	T
Polyphen		0.049	B
Vest4		0.044
MVP		0.33
MPC		0.0082
ClinPred		0.0066	T
GERP RS		1.8
Varity_R		0.066
gMVP		0.49
Mutation Taster		=97/3	polymorphism (auto)

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: rs143515399; hg19: chrX-54776479;