NM_000354.6:c.1016C>T

Variant names:

• chrX-106034263-G-A
• rs151001785
• NM_000354.6:c.1016C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_000354.6(SERPINA7):​c.1016C>T​(p.Thr339Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,208,935 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50
• 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: Likely_benign. The variant received -1 ACMG points.

• 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.

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.1016C>T	p.Thr339Ile	missense	Exon 4 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.1016C>T	p.Thr339Ile	missense	Exon 4 of 5	ENSP00000361644.1	P05543
	SERPINA7	ENST00000327674.8	TSL:1	c.1016C>T	p.Thr339Ile	missense	Exon 3 of 4	ENSP00000329374.4	P05543
	SERPINA7	ENST00000907820.1		c.1016C>T	p.Thr339Ile	missense	Exon 4 of 5	ENSP00000577879.1

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 112050 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000129

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

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182709 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1096885 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 2 AN XY: 362485

African (AFR) AF: 0.000228 AC: 6 AN: 26347

American (AMR) AF: 0.00 AC: 0 AN: 35152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19360

East Asian (EAS) AF: 0.00 AC: 0 AN: 30186

South Asian (SAS) AF: 0.00 AC: 0 AN: 54108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841029

Other (OTH) AF: 0.00 AC: 0 AN: 46046

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 112050 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34246

African (AFR) AF: 0.000129 AC: 4 AN: 30896

American (AMR) AF: 0.00 AC: 0 AN: 10524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3523

South Asian (SAS) AF: 0.00 AC: 0 AN: 2715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53183

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.5
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.85	P
Vest4		0.25
MVP		0.62
MPC		0.18
ClinPred		0.97	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.48
Mutation Taster		=74/26	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: rs151001785; hg19: chrX-105278254;