Genetic Variant NM_198510.3:c.3719G>A (chrX-54751014-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_198510.3(ITIH6):c.3719G>A(p.Arg1240His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,158,890 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1240G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000028 ( 0 hom. 14 hem. )

Consequence

ITIH6
NM_198510.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.239

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.045235902).

BS2

High Hemizygotes 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.3719G>A	p.Arg1240His	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.3719G>A	p.Arg1240His	missense	Exon 12 of 13	ENSP00000218436.6	Q6UXX5

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

112192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000940

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000554

AC:

AN:

108305

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.000481

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:

0.0000277

AC:

AN:

1046698

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

334846

show subpopulations

African (AFR)

AF:

0.000473

AC:

AN:

25351

American (AMR)

AF:

0.00

AC:

AN:

27139

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17429

East Asian (EAS)

AF:

0.0000354

AC:

AN:

28228

South Asian (SAS)

AF:

0.000168

AC:

AN:

47698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37601

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3995

European-Non Finnish (NFE)

AF:

0.00000981

AC:

AN:

815247

Other (OTH)

AF:

0.00

AC:

AN:

44010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000107

AC:

AN:

112192

Hom.:

Cov.:

AF XY:

0.0000873

AC XY:

AN XY:

34356

show subpopulations

African (AFR)

AF:

0.000356

AC:

AN:

30862

American (AMR)

AF:

0.0000940

AC:

AN:

10640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2673

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6165

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53207

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000525

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000267

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

0.072

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.013

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.0032

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.53

M_CAP

Benign

0.0045

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PhyloP100

-0.24

PrimateAI

Benign

0.41

PROVEAN

Benign

1.1

REVEL

Benign

0.059

Sift

Benign

1.0

Sift4G

Benign

0.27

Polyphen

0.0030

Vest4

0.068

MVP

0.43

MPC

0.0079

ClinPred

0.025

GERP RS

-4.4

Varity_R

0.025

gMVP

0.32

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over