X-106033624-T-C

Variant names:

• chrX-106033624-T-C
• NM_000354.6:c.1124A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000354.6(SERPINA7):​c.1124A>G​(p.Gln375Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,014 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042202264).

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.1124A>G	p.Gln375Arg	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.1124A>G	p.Gln375Arg	missense	Exon 5 of 5	ENSP00000361644.1	P05543
	SERPINA7	ENST00000327674.8	TSL:1	c.1124A>G	p.Gln375Arg	missense	Exon 4 of 4	ENSP00000329374.4	P05543
	SERPINA7	ENST00000907820.1		c.1154A>G	p.Gln385Arg	missense	Exon 5 of 5	ENSP00000577879.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098014 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363460

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841952

Other (OTH) AF: 0.00 AC: 0 AN: 46085

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

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	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.7
DANN	Benign	0.50
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.78	N
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.0030	B
Vest4		0.024
MutPred		0.49		Gain of phosphorylation at S373 (P = 0.086)
MVP		0.39
MPC		0.027
ClinPred		0.035	T
GERP RS		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.20
Mutation Taster		=98/2	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

hg19: chrX-105277615;