rs2234036

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_000354.6(SERPINA7):c.631G>A(p.Ala211Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,208,749 control chromosomes in the GnomAD database, including 25 homozygotes. There are 1,141 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., 79 hem., cov: 23)

Exomes 𝑓: 0.0020 ( 24 hom. 1062 hem. )

Consequence

SERPINA7
NM_000354.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: 1.30

Publications

10 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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046699643).

BP6

Variant X-106035377-C-T is Benign according to our data. Variant chrX-106035377-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9784.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00156 (175/112320) while in subpopulation SAS AF = 0.0258 (71/2749). AF 95% confidence interval is 0.021. There are 1 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 79 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000354.6. 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
	SERPINA7	NM_000354.6	MANE Select	c.631G>A	p.Ala211Thr	missense	Exon 3 of 5	NP_000345.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SERPINA7	ENST00000372563.2	TSL:5 MANE Select	c.631G>A	p.Ala211Thr	missense	Exon 3 of 5	ENSP00000361644.1
SERPINA7	ENST00000327674.8	TSL:1	c.631G>A	p.Ala211Thr	missense	Exon 2 of 4	ENSP00000329374.4
SERPINA7	ENST00000907820.1		c.631G>A	p.Ala211Thr	missense	Exon 3 of 5	ENSP00000577879.1

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

178

AN:

112268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.00487

AC:

889

AN:

182391

AF XY:

0.00602

show subpopulations

Gnomad AFR exome

AF:

0.00114

Gnomad AMR exome

AF:

0.0000731

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0139

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.00355

GnomAD4 exome

AF:

0.00203

AC:

2225

AN:

1096429

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

1062

AN XY:

362019

show subpopulations

African (AFR)

AF:

0.000607

AC:

AN:

26348

American (AMR)

AF:

0.0000569

AC:

AN:

35173

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19348

East Asian (EAS)

AF:

0.00898

AC:

271

AN:

30189

South Asian (SAS)

AF:

0.0302

AC:

1634

AN:

54095

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40503

Middle Eastern (MID)

AF:

0.00194

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

840616

Other (OTH)

AF:

0.00443

AC:

204

AN:

46026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

139

208

278

347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00156

AC:

175

AN:

112320

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

AN XY:

34554

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

30982

American (AMR)

AF:

0.000189

AC:

AN:

10588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.0156

AC:

AN:

3528

South Asian (SAS)

AF:

0.0258

AC:

AN:

2749

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6195

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000752

AC:

AN:

53192

Other (OTH)

AF:

0.00130

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000329

Hom.:

Bravo

AF:

0.00114

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00156

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00529

AC:

642

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

SERPINA7-related disorder (1)

Thyroxine-binding globulin deficiency (1)

Thyroxine-binding globulin, variant A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.030

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.6

PhyloP100

1.3

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.40

REVEL

Uncertain

0.50

Sift

Benign

0.27

Sift4G

Benign

0.16

Polyphen

0.10

Vest4

0.64

MVP

0.87

MPC

0.030

ClinPred

0.0083

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.53

Mutation Taster

=52/48

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over