X-106036488-C-T

Variant names:

• chrX-106036488-C-T
• rs1050086
• NM_000354.6:c.571G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_000354.6(SERPINA7):​c.571G>A​(p.Asp191Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,208,900 control chromosomes in the GnomAD database, including 265 homozygotes. There are 1,982 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.031 (140 hom., 956 hem., cov: 22)
  • Exomes 𝑓: 0.0034 (125 hom. 1026 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0800
• Publications: 7 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: Benign. The variant received -8 ACMG points.

• PP5: Variant X-106036488-C-T is Pathogenic according to our data. Variant chrX-106036488-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9786.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018774569). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

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.571G>A	p.Asp191Asn	missense	Exon 2 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.571G>A	p.Asp191Asn	missense	Exon 2 of 5	ENSP00000361644.1	P05543
	SERPINA7	ENST00000327674.8	TSL:1	c.571G>A	p.Asp191Asn	missense	Exon 1 of 4	ENSP00000329374.4	P05543
	SERPINA7	ENST00000907820.1		c.571G>A	p.Asp191Asn	missense	Exon 2 of 5	ENSP00000577879.1

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 3503 AN: 111560 Hom.: 140 Cov.: 22

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

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: 0.000395

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.00922 AC: 1687 AN: 182890 AF XY: 0.00656

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00742

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000331

Gnomad OTH exome AF: 0.00421

GnomAD4 exome AF: 0.00344 AC: 3779 AN: 1097283 Hom.: 125 Cov.: 30 AF XY: 0.00283 AC XY: 1026 AN XY: 362877

African (AFR) AF: 0.111 AC: 2915 AN: 26360

American (AMR) AF: 0.00816 AC: 287 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54101

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

Middle Eastern (MID) AF: 0.00460 AC: 19 AN: 4129

European-Non Finnish (NFE) AF: 0.000204 AC: 172 AN: 841383

Other (OTH) AF: 0.00803 AC: 370 AN: 46054

GnomAD4 genome AF: 0.0314 AC: 3507 AN: 111617 Hom.: 140 Cov.: 22 AF XY: 0.0282 AC XY: 956 AN XY: 33895

African (AFR) AF: 0.108 AC: 3307 AN: 30685

American (AMR) AF: 0.0131 AC: 138 AN: 10521

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2669

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000395 AC: 21 AN: 53105

Other (OTH) AF: 0.0264 AC: 40 AN: 1515

Alfa AF: 0.0104 Hom.: 421

Bravo AF: 0.0364

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.105 AC: 401

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.0103 AC: 1244

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Thyroxine-binding globulin, slow (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.080
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	0.38	T
Polyphen		0.0050	B
Vest4		0.045
MPC		0.027
ClinPred		0.0052	T
GERP RS		2.7
Varity_R		0.30
gMVP		0.25
Mutation Taster		=98/2	disease causing (ClinVar)

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: rs1050086; hg19: chrX-105280479; COSMIC: COSV59666226; COSMIC: COSV59666226;