NM_000354.6:c.1055A>T

Variant names:

• chrX-106033693-T-A
• rs149192322
• NM_000354.6:c.1055A>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The NM_000354.6(SERPINA7):​c.1055A>T​(p.Lys352Met) variant causes a missense change. The variant allele was found at a frequency of 0.000639 in 1,208,978 control chromosomes in the GnomAD database, including 3 homozygotes. There are 225 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., 117 hem., cov: 23)
  • Exomes 𝑓: 0.00036 (2 hom. 108 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.78
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017669857).
• BP6: Variant X-106033693-T-A is Benign according to our data. Variant chrX-106033693-T-A is described in ClinVar as Benign. ClinVar VariationId is 709644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 117 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1055A>T	p.Lys352Met	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.1055A>T	p.Lys352Met	missense	Exon 5 of 5	ENSP00000361644.1	P05543
	SERPINA7	ENST00000327674.8	TSL:1	c.1055A>T	p.Lys352Met	missense	Exon 4 of 4	ENSP00000329374.4	P05543
	SERPINA7	ENST00000907820.1		c.1085A>T	p.Lys362Met	missense	Exon 5 of 5	ENSP00000577879.1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 381 AN: 111563 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00219

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: 0.0000753

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.000983 AC: 180 AN: 183070 AF XY: 0.000636

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000358 AC: 393 AN: 1097362 Hom.: 2 Cov.: 30 AF XY: 0.000298 AC XY: 108 AN XY: 362868

African (AFR) AF: 0.0107 AC: 282 AN: 26365

American (AMR) AF: 0.00131 AC: 46 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4131

European-Non Finnish (NFE) AF: 0.0000214 AC: 18 AN: 841395

Other (OTH) AF: 0.000912 AC: 42 AN: 46062

GnomAD4 genome AF: 0.00340 AC: 380 AN: 111616 Hom.: 1 Cov.: 23 AF XY: 0.00346 AC XY: 117 AN XY: 33860

African (AFR) AF: 0.0114 AC: 350 AN: 30719

American (AMR) AF: 0.00219 AC: 23 AN: 10492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3516

South Asian (SAS) AF: 0.00 AC: 0 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6091

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000753 AC: 4 AN: 53096

Other (OTH) AF: 0.00197 AC: 3 AN: 1523

Alfa AF: 0.000803 Hom.: 18

Bravo AF: 0.00399

ESP6500AA AF: 0.0117 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00131 AC: 159

ClinVar

ClinVar submissions

Significance: Benign

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	0.32
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.018	T
MetaSVM	Pathogenic	0.89	D
PhyloP100		3.8
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.19
MVP		0.98
MPC		0.22
ClinPred		0.10	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.70
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149192322; hg19: chrX-105277684;