X-106033506-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000354.6(SERPINA7):c.1242A>C(p.Glu414Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000944 in 1,209,264 control chromosomes in the GnomAD database, including 10 homozygotes. There are 343 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., 154 hem., cov: 23)
  • Exomes 𝑓: 0.00055 (4 hom. 189 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.778

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030000508).
• BP6: Variant X-106033506-T-G is Benign according to our data. Variant chrX-106033506-T-G is described in ClinVar as [Benign]. Clinvar id is 777816.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00477 (534/111864) while in subpopulation AFR AF= 0.0164 (506/30805). AF 95% confidence interval is 0.0152. There are 6 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA7	NM_000354.6	c.1242A>C	p.Glu414Asp	missense_variant	5/5	ENST00000372563.2
SERPINA7	XM_006724683.3	c.1272A>C	p.Glu424Asp	missense_variant	5/5
SERPINA7	XM_005262180.5	c.*187A>C		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA7	ENST00000372563.2	c.1242A>C	p.Glu414Asp	missense_variant	5/5	5	NM_000354.6	P1
SERPINA7	ENST00000327674.8	c.1242A>C	p.Glu414Asp	missense_variant	4/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 536 AN: 111814 Hom.: 6 Cov.: 23 AF XY: 0.00453 AC XY: 154 AN XY: 34028

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00200

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: 0.00200

GnomAD3 exomes AF: 0.00152 AC: 277 AN: 182829 Hom.: 1 AF XY: 0.00107 AC XY: 72 AN XY: 67527

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000553 AC: 607 AN: 1097400 Hom.: 4 Cov.: 30 AF XY: 0.000521 AC XY: 189 AN XY: 362948

Gnomad4 AFR exome AF: 0.0190

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000143

Gnomad4 OTH exome AF: 0.000999

GnomAD4 genome AF: 0.00477 AC: 534 AN: 111864 Hom.: 6 Cov.: 23 AF XY: 0.00452 AC XY: 154 AN XY: 34088

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000753

Gnomad4 OTH AF: 0.00198

Alfa AF: 0.000648 Hom.: 18

Bravo AF: 0.00609

ESP6500AA AF: 0.0156 AC: 60

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00153 AC: 186

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	11
Dann	Benign	0.89
DEOGEN2	Benign	0.019	T;T
FATHMM_MKL	Benign	0.29	N
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.17
Sift	Benign	0.29	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.17		Gain of phosphorylation at T413 (P = 0.1679);Gain of phosphorylation at T413 (P = 0.1679);
MVP		0.33
MPC		0.024
ClinPred		0.0020	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61730548; hg19: chrX-105277497;