rs587776719

Variant names:

• chrX-106033633-AG-A
• rs587776719
• NM_000354.6:c.1114delC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PVS1_Strong BS2_Supporting

The NM_000354.6(SERPINA7):​c.1114delC​(p.Leu372PhefsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,098,018 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000023 (0 hom. 7 hem.)
• Consequence: SERPINA7 NM_000354.6 frameshift
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.390
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.107 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BS2: High Hemizygotes in GnomAdExome4 at 7 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.1114delC	p.Leu372PhefsTer23	frameshift_variant	Exon 5 of 5	ENST00000372563.2	NP_000345.2
SERPINA7	XM_006724683.3	c.1144delC	p.Leu382PhefsTer23	frameshift_variant	Exon 5 of 5		XP_006724746.1
SERPINA7	XM_005262180.5	c.*59delC		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.1114delC	p.Leu372PhefsTer23	frameshift_variant	Exon 5 of 5	5	NM_000354.6	ENSP00000361644.1
SERPINA7	ENST00000327674.8	c.1114delC	p.Leu372PhefsTer23	frameshift_variant	Exon 4 of 4	1		ENSP00000329374.4
SERPINA7	ENST00000487487.1	n.*53delC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000219 AC: 4 AN: 182922 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000289

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1098018 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 363466

African (AFR) AF: 0.00 AC: 0 AN: 26384

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.000828 AC: 25 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841950

Other (OTH) AF: 0.00 AC: 0 AN: 46089

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

Jun 01, 1996

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
PhyloP100		0.39
Mutation Taster		=72/128	disease causing

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

Other links and lift over

dbSNP: rs587776719; hg19: chrX-105277624;