dbSNP rs72554658: SERPINA7:p.Pro383Leu (chrX-106033600-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000354.6(SERPINA7):c.1148C>T(p.Pro383Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,547 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

SERPINA7
NM_000354.6 missense

Scores

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 2.28

Publications

4 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.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SERPINA7	NM_000354.6 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 5 of 5	ENST00000372563.2	NP_000345.2
SERPINA7	XM_006724683.3 link	c.1178C>T	p.Pro393Leu	missense_variant	Exon 5 of 5		XP_006724746.1
SERPINA7	XM_005262180.5 link	c.*93C>T		3_prime_UTR_variant	Exon 5 of 5		XP_005262237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SERPINA7	ENST00000372563.2 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 5 of 5	5	NM_000354.6	ENSP00000361644.1
SERPINA7	ENST00000327674.8 link	c.1148C>T	p.Pro383Leu	missense_variant	Exon 4 of 4	1		ENSP00000329374.4
SERPINA7	ENST00000487487.1 link	n.*87C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000547

AC:

AN:

182762

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000761

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:

9.11e-7

AC:

AN:

1097547

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363001

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26376

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841517

Other (OTH)

AF:

0.00

AC:

AN:

46074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Thyroxine-binding globulin quantitative trait locus

Other:1

Feb 01, 1996

OMIM

Significance:association

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.20

T;T

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.73

.;T

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.7

L;L

PhyloP100

2.3

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.53

Sift

Benign

0.035

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.61

P;P

Vest4

0.35

MutPred

0.76

Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);

MVP

0.70

MPC

0.17

ClinPred

0.26

GERP RS

2.2

Varity_R

0.28

gMVP

0.41

Mutation Taster

=19/81

disease causing

(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