X-106033624-T-C

Position:

• chrX-106033624-T-C

Variant summary

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

The NM_000354.6(SERPINA7):​c.1124A>G​(p.Gln375Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,014 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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=0.042202264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA7	NM_000354.6	c.1124A>G	p.Gln375Arg	missense_variant	5/5	ENST00000372563.2	NP_000345.2
SERPINA7	XM_006724683.3	c.1154A>G	p.Gln385Arg	missense_variant	5/5		XP_006724746.1
SERPINA7	XM_005262180.5	c.*69A>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	c.1124A>G	p.Gln375Arg	missense_variant	5/5	5	NM_000354.6	ENSP00000361644.1
SERPINA7	ENST00000327674.8	c.1124A>G	p.Gln375Arg	missense_variant	4/4	1		ENSP00000329374.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098014 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2024

The c.1124A>G (p.Q375R) 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 1124, causing the glutamine (Q) at amino acid position 375 to be replaced by an arginine (R). 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	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.7
DANN	Benign	0.50
DEOGEN2	Benign	0.021	T;T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.32	.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.78	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0030	B;B
Vest4		0.024
MutPred		0.49		Gain of phosphorylation at S373 (P = 0.086);Gain of phosphorylation at S373 (P = 0.086);
MVP		0.39
MPC		0.027
ClinPred		0.035	T
GERP RS		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.20

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-105277615;