chrX-106033549-G-T

Variant names:

• chrX-106033549-G-T
• NM_000354.6:c.1199C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000354.6(SERPINA7):​c.1199C>A​(p.Thr400Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA7	NM_000354.6	c.1199C>A	p.Thr400Lys	missense_variant	Exon 5 of 5	ENST00000372563.2	NP_000345.2
SERPINA7	XM_006724683.3	c.1229C>A	p.Thr410Lys	missense_variant	Exon 5 of 5		XP_006724746.1
SERPINA7	XM_005262180.5	c.*144C>A		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.1199C>A	p.Thr400Lys	missense_variant	Exon 5 of 5	5	NM_000354.6	ENSP00000361644.1
SERPINA7	ENST00000327674.8	c.1199C>A	p.Thr400Lys	missense_variant	Exon 4 of 4	1		ENSP00000329374.4
SERPINA7	ENST00000487487.1	n.*138C>A		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

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1199C>A (p.T400K) alteration is located in exon 5 (coding exon 4) of the SERPINA7 gene. This alteration results from a C to A substitution at nucleotide position 1199, causing the threonine (T) at amino acid position 400 to be replaced by a lysine (K). 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	.;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.51
MutPred		0.71		Gain of methylation at T400 (P = 0.0124);Gain of methylation at T400 (P = 0.0124);
MVP		0.60
MPC		0.22
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-105277540;