X-106033622-G-C

Variant names:

• chrX-106033622-G-C
• NM_000354.6:c.1126C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000354.6(SERPINA7):​c.1126C>G​(p.Pro376Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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: not found (cov: 23)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06381631).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA7	NM_000354.6	c.1126C>G	p.Pro376Ala	missense_variant	Exon 5 of 5	ENST00000372563.2	NP_000345.2
SERPINA7	XM_006724683.3	c.1156C>G	p.Pro386Ala	missense_variant	Exon 5 of 5		XP_006724746.1
SERPINA7	XM_005262180.5	c.*71C>G		3_prime_UTR_variant	Exon 5 of 5		XP_005262237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA7	ENST00000372563.2	c.1126C>G	p.Pro376Ala	missense_variant	Exon 5 of 5	5	NM_000354.6	ENSP00000361644.1
SERPINA7	ENST00000327674.8	c.1126C>G	p.Pro376Ala	missense_variant	Exon 4 of 4	1		ENSP00000329374.4
SERPINA7	ENST00000487487.1	n.*65C>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1126C>G (p.P376A) alteration is located in exon 5 (coding exon 4) of the SERPINA7 gene. This alteration results from a C to G substitution at nucleotide position 1126, causing the proline (P) at amino acid position 376 to be replaced by an alanine (A). 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	0.072
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.7
DANN	Benign	0.085
DEOGEN2	Benign	0.019	T;T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.35	.;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.73	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.20
Sift	Benign	0.40	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.36		Loss of disorder (P = 0.069);Loss of disorder (P = 0.069);
MVP		0.59
MPC		0.025
ClinPred		0.028	T
GERP RS		0.12
Varity_R		0.086
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-105277613;