rs28937312

Variant names:

• chrX-106035268-A-G
• rs28937312
• NM_000354.6:c.740T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_Strong BS2_Supporting

The NM_000354.6(SERPINA7):​c.740T>C​(p.Leu247Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,608 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.484

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 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• BS2: High Hemizygotes in GnomAdExome4 at 2 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 rank	MANE	Protein	UniProt
SERPINA7	NM_000354.6	c.740T>C	p.Leu247Pro	missense_variant	Exon 3 of 5	ENST00000372563.2	NP_000345.2
SERPINA7	XM_006724683.3	c.740T>C	p.Leu247Pro	missense_variant	Exon 3 of 5		XP_006724746.1
SERPINA7	XM_005262180.5	c.740T>C	p.Leu247Pro	missense_variant	Exon 3 of 5		XP_005262237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA7	ENST00000372563.2	c.740T>C	p.Leu247Pro	missense_variant	Exon 3 of 5	5	NM_000354.6	ENSP00000361644.1
SERPINA7	ENST00000327674.8	c.740T>C	p.Leu247Pro	missense_variant	Exon 2 of 4	1		ENSP00000329374.4
SERPINA7	ENST00000487487.1	n.13T>C		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182846 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097608 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363110

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: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Thyroxine-binding globulin quantitative trait locus Other:1

Mar 01, 1992

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.49	.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.63
Sift	Benign	0.13	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.83	P;P
Vest4		0.64
MutPred		0.88		Loss of stability (P = 0.0238);Loss of stability (P = 0.0238);
MVP		0.93
MPC		0.24
ClinPred		0.87	D
GERP RS		3.2
Varity_R		0.96
gMVP		0.95

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

Other links and lift over

dbSNP: rs28937312; hg19: chrX-105279259;