X-106036712-A-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PP3_StrongPP5BS2_Supporting

The NM_000354.6(SERPINA7):c.347T>A(p.Ile116Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,209,141 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 Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

SERPINA7
NM_000354.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.56

Publications

5 publications found

Variant links:

Genes affected

SERPINA7 (HGNC:11583): (serpin family A member 7) There are three proteins including thyroxine-binding globulin (TBG), transthyretin and albumin responsible for carrying the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in the bloodstream. This gene encodes the major thyroid hormone transport protein, TBG, in serum. It belongs to the serpin family in genomics, but the protein has no inhibitory function like many other members of the serpin family. Mutations in this gene result in TGB deficiency, which has been classified as partial deficiency, complete deficiency, and excess, based on the level of serum TBG. Alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of these variants has not been determined.[provided by RefSeq, Jun 2012]

SERPINA7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine; in variant Gary (size 0) in uniprot entity THBG_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant X-106036712-A-T is Pathogenic according to our data. Variant chrX-106036712-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9790.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA7	NM_000354.6 link	c.347T>A	p.Ile116Asn	missense_variant	Exon 2 of 5	ENST00000372563.2	NP_000345.2	P05543
SERPINA7	XM_006724683.3 link	c.347T>A	p.Ile116Asn	missense_variant	Exon 2 of 5		XP_006724746.1
SERPINA7	XM_005262180.5 link	c.347T>A	p.Ile116Asn	missense_variant	Exon 2 of 5		XP_005262237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA7	ENST00000372563.2 link	c.347T>A	p.Ile116Asn	missense_variant	Exon 2 of 5	5	NM_000354.6	ENSP00000361644.1		P05543
SERPINA7	ENST00000327674.8 link	c.347T>A	p.Ile116Asn	missense_variant	Exon 1 of 4	1		ENSP00000329374.4		P05543

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111242

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:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097899

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363403

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26383

American (AMR)

AF:

0.00

AC:

AN:

35162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30198

South Asian (SAS)

AF:

0.00

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

841903

Other (OTH)

AF:

0.00

AC:

AN:

46082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111242

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30618

American (AMR)

AF:

0.00

AC:

AN:

10446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3510

South Asian (SAS)

AF:

0.00

AC:

AN:

2633

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52931

Other (OTH)

AF:

0.00

AC:

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Thyroxine-binding globulin deficiency, partial

Pathogenic:1

Mar 01, 1990

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

.;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.5

L;L

PhyloP100

6.6

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.90

Gain of catalytic residue at I116 (P = 0.0034);Gain of catalytic residue at I116 (P = 0.0034);

MVP

0.96

MPC

0.25

ClinPred

1.0

GERP RS

4.9

Varity_R

0.90

gMVP

0.59

Mutation Taster

=9/91

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over