dbSNP rs28933689: SERPINA7:p.Ile116Thr (chrX-106036712-A-G) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000354.6(SERPINA7):c.347T>C(p.Ile116Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,899 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I116N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

SERPINA7
NM_000354.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.56

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA7	NM_000354.6 link	c.347T>C	p.Ile116Thr	missense_variant	Exon 2 of 5	ENST00000372563.2	NP_000345.2	P05543
SERPINA7	XM_006724683.3 link	c.347T>C	p.Ile116Thr	missense_variant	Exon 2 of 5		XP_006724746.1
SERPINA7	XM_005262180.5 link	c.347T>C	p.Ile116Thr	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>C	p.Ile116Thr	missense_variant	Exon 2 of 5	5	NM_000354.6	ENSP00000361644.1		P05543
SERPINA7	ENST00000327674.8 link	c.347T>C	p.Ile116Thr	missense_variant	Exon 1 of 4	1		ENSP00000329374.4		P05543

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097899

Hom.:

Cov.:

AF XY:

0.00

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:

0.0000516

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:

0.00

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

.;T

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.8

L;L

PhyloP100

6.6

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.99

D;D

Vest4

0.48

MutPred

0.80

Loss of stability (P = 0.0299);Loss of stability (P = 0.0299);

MVP

0.67

MPC

0.22

ClinPred

0.96

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.28

Mutation Taster

=25/75

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over