X-106034370-C-G

Variant names:

• chrX-106034370-C-G
• rs1804495
• NM_000354.6:c.909G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000354.6(SERPINA7):​c.909G>C​(p.Leu303Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,809 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: SERPINA7 NM_000354.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3010076).

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.909G>C	p.Leu303Phe	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.909G>C	p.Leu303Phe	missense	Exon 4 of 5	ENSP00000361644.1	P05543
	SERPINA7	ENST00000327674.8	TSL:1	c.909G>C	p.Leu303Phe	missense	Exon 3 of 4	ENSP00000329374.4	P05543
	SERPINA7	ENST00000907820.1		c.909G>C	p.Leu303Phe	missense	Exon 4 of 5	ENSP00000577879.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093809 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 359651

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26286

American (AMR) AF: 0.00 AC: 0 AN: 35114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19326

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.00 AC: 0 AN: 54033

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40513

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 838342

Other (OTH) AF: 0.00 AC: 0 AN: 45908

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		-1.1
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.020	D
Polyphen		0.98	D
Vest4		0.17
MutPred		0.30		Gain of methylation at K298 (P = 0.093)
MVP		0.75
MPC		0.15
ClinPred		0.72	D
GERP RS		2.5
Varity_R		0.82
gMVP		0.68
Mutation Taster		=70/30	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: rs1804495; hg19: chrX-105278361;