X-106033560-C-A

Variant names:

• chrX-106033560-C-A
• rs1057524273
• NM_000354.6:c.1188G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000354.6(SERPINA7):​c.1188G>T​(p.Leu396Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,222 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0430
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13770723).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000354.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA7	NM_000354.6	MANE Select	c.1188G>T	p.Leu396Phe	missense	Exon 5 of 5	NP_000345.2	P05543

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA7	ENST00000372563.2	TSL:5 MANE Select	c.1188G>T	p.Leu396Phe	missense	Exon 5 of 5	ENSP00000361644.1	P05543
	SERPINA7	ENST00000327674.8	TSL:1	c.1188G>T	p.Leu396Phe	missense	Exon 4 of 4	ENSP00000329374.4	P05543
	SERPINA7	ENST00000907820.1		c.1218G>T	p.Leu406Phe	missense	Exon 5 of 5	ENSP00000577879.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 112008 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097214 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362696

African (AFR) AF: 0.0000379 AC: 1 AN: 26371

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54129

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841226

Other (OTH) AF: 0.00 AC: 0 AN: 46057

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 112008 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34218

African (AFR) AF: 0.0000324 AC: 1 AN: 30823

American (AMR) AF: 0.00 AC: 0 AN: 10553

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53200

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.74	N
PhyloP100		-0.043
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.26
Sift	Benign	0.21	T
Sift4G	Benign	0.60	T
Polyphen		0.046	B
Vest4		0.050
MutPred		0.44		Gain of MoRF binding (P = 0.1675)
MVP		0.73
MPC		0.21
ClinPred		0.49	T
GERP RS		2.2
Varity_R		0.33
gMVP		0.14
Mutation Taster		=65/35	polymorphism

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: rs1057524273; hg19: chrX-105277551;