X-106034334-G-T

Position:

chrX-106034334-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_000354.6(SERPINA7):c.945C>A(p.Asp315Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,205,346 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000032 ( 0 hom. 12 hem. )

Consequence

SERPINA7
NM_000354.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.66

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:

SERPINA7 (HGNC:):

SERPINA7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.038569838).

BS2

High Hemizygotes in GnomAdExome4 at 12 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	UniProt
SERPINA7	NM_000354.6 linkuse as main transcript	c.945C>A	p.Asp315Glu	missense_variant	4/5	ENST00000372563.2	NP_000345.2	P05543
SERPINA7	XM_006724683.3 linkuse as main transcript	c.945C>A	p.Asp315Glu	missense_variant	4/5		XP_006724746.1
SERPINA7	XM_005262180.5 linkuse as main transcript	c.945C>A	p.Asp315Glu	missense_variant	4/5		XP_005262237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SERPINA7	ENST00000372563.2 linkuse as main transcript	c.945C>A	p.Asp315Glu	missense_variant	4/5	5	NM_000354.6	ENSP00000361644.1	P05543
SERPINA7	ENST00000327674.8 linkuse as main transcript	c.945C>A	p.Asp315Glu	missense_variant	3/4	1		ENSP00000329374.4	P05543
SERPINA7	ENST00000487487.1 linkuse as main transcript	n.218C>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111839

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34057

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:

0.000284

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000820

AC:

AN:

182852

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

67528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00108

Gnomad SAS 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:

0.0000320

AC:

AN:

1093507

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

359207

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00113

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111839

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34057

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000284

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The c.945C>A (p.D315E) alteration is located in exon 4 (coding exon 3) of the SERPINA7 gene. This alteration results from a C to A substitution at nucleotide position 945, causing the aspartic acid (D) at amino acid position 315 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.8

DANN

Benign

0.96

DEOGEN2

Benign

0.062

T;T

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.17

Sift

Benign

0.30

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.033

B;B

Vest4

0.051

MutPred

0.64

Loss of catalytic residue at D315 (P = 0.0661);Loss of catalytic residue at D315 (P = 0.0661);

MVP

0.52

MPC

0.025

ClinPred

0.044

GERP RS

-4.0

Varity_R

0.21

gMVP

0.48

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

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