Genetic Variant NM_198510.3:c.3550A>G (chrX-54751183-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198510.3(ITIH6):c.3550A>G(p.Arg1184Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,210,000 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

ITIH6
NM_198510.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.720

Publications

0 publications found

Variant links:

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]

ITIH6 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.076015174).

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.3550A>G	p.Arg1184Gly	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.3550A>G	p.Arg1184Gly	missense	Exon 12 of 13	ENSP00000218436.6	Q6UXX5

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112227

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181104

AF XY:

0.00

show subpopulations

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:

0.0000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097773

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363133

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26399

American (AMR)

AF:

0.00

AC:

AN:

35179

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54037

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841852

Other (OTH)

AF:

0.00

AC:

AN:

46078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112227

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34411

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30923

American (AMR)

AF:

0.00

AC:

AN:

10661

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2691

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6127

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53202

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0030

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.51

M_CAP

Benign

0.0060

MetaRNN

Benign

0.076

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

PhyloP100

0.72

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

REVEL

Benign

0.089

Sift

Benign

0.24

Sift4G

Uncertain

0.010

Polyphen

0.0050

Vest4

0.22

MutPred

0.48

Gain of catalytic residue at Q1186 (P = 0.0339)

MVP

0.11

MPC

0.014

ClinPred

0.082

GERP RS

2.4

Varity_R

0.18

gMVP

0.71

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over