X-106033598-T-C

Position:

chrX-106033598-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_000354.6(SERPINA7):c.1150A>G(p.Ile384Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000711 in 1,209,288 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.000039 ( 0 hom. 11 hem. )

Consequence

SERPINA7
NM_000354.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -1.26

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01921755).

BP6

Variant X-106033598-T-C is Benign according to our data. Variant chrX-106033598-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1134042.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 9 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/exons	MANE	Protein
SERPINA7	NM_000354.6 linkuse as main transcript	c.1150A>G	p.Ile384Val	missense_variant	5/5	ENST00000372563.2	NP_000345.2
SERPINA7	XM_006724683.3 linkuse as main transcript	c.1180A>G	p.Ile394Val	missense_variant	5/5		XP_006724746.1
SERPINA7	XM_005262180.5 linkuse as main transcript	c.*95A>G		3_prime_UTR_variant	5/5		XP_005262237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA7	ENST00000372563.2 linkuse as main transcript	c.1150A>G	p.Ile384Val	missense_variant	5/5	5	NM_000354.6	ENSP00000361644	P1
SERPINA7	ENST00000327674.8 linkuse as main transcript	c.1150A>G	p.Ile384Val	missense_variant	4/4	1		ENSP00000329374	P1

Frequencies

GnomAD3 genomes

AF:

0.000385

AC:

AN:

111724

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

AN XY:

33942

show subpopulations

Gnomad AFR

AF:

0.00127

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000951

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000985

AC:

AN:

182743

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

67519

show subpopulations

Gnomad AFR exome

AF:

0.000989

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000392

AC:

AN:

1097564

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

363020

show subpopulations

Gnomad4 AFR exome

AF:

0.00106

Gnomad4 AMR exome

AF:

0.0000852

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000385

AC:

AN:

111724

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

AN XY:

33942

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.0000951

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000295

Hom.:

Bravo

AF:

0.000408

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000123

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.1150A>G (p.I384V) alteration is located in exon 5 (coding exon 4) of the SERPINA7 gene. This alteration results from a A to G substitution at nucleotide position 1150, causing the isoleucine (I) at amino acid position 384 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SERPINA7-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.16

DANN

Benign

0.22

DEOGEN2

Benign

0.023

T;T

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.58

.;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

0.31

N;N

REVEL

Benign

0.12

Sift

Benign

0.90

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0

B;B

Vest4

0.036

MVP

0.69

MPC

0.024

ClinPred

0.014

GERP RS

1.0

Varity_R

0.14

gMVP

0.093

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over