14-94614811-C-G

Position:

• chr14-94614811-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001085.5(SERPINA3):​c.370C>G​(p.Arg124Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINA3 NM_001085.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.17

Genes affected

SERPINA3 (HGNC:16): (serpin family A member 3) The protein encoded by this gene is a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. This gene is one in a cluster of serpin genes located on the q arm of chromosome 14. Polymorphisms in this protein appear to be tissue specific and influence protease targeting. Variations in this protein's sequence have been implicated in Alzheimer's disease, and deficiency of this protein has been associated with liver disease. Mutations have been identified in patients with Parkinson disease and chronic obstructive pulmonary disease. [provided by RefSeq, Jun 2020]

ENSG00000273259 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA3	NM_001085.5	c.370C>G	p.Arg124Gly	missense_variant	2/5	ENST00000393078.5	NP_001076.2
SERPINA3	NM_001384672.1	c.370C>G	p.Arg124Gly	missense_variant	2/5		NP_001371601.1
SERPINA3	NM_001384673.1	c.370C>G	p.Arg124Gly	missense_variant	3/6		NP_001371602.1
SERPINA3	NM_001384674.1	c.370C>G	p.Arg124Gly	missense_variant	3/6		NP_001371603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA3	ENST00000393078.5	c.370C>G	p.Arg124Gly	missense_variant	2/5	1	NM_001085.5	ENSP00000376793.3
ENSG00000273259	ENST00000553947.1	n.*1196C>G		non_coding_transcript_exon_variant	5/8	2		ENSP00000452367.2
ENSG00000273259	ENST00000553947.1	n.*1196C>G		3_prime_UTR_variant	5/8	2		ENSP00000452367.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The SERPINA3 p.Arg124Gly variant was not identified in the literature nor was it identified in dbSNP, ClinVar or in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). The p.Arg124 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	0.0037	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	D;D;.;D
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.78	T;.;T;.
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.4	L;L;.;L
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.036	D;D;T;D
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.52	P;P;.;P
Vest4		0.073
MutPred		0.55		Gain of catalytic residue at L123 (P = 0.0203);Gain of catalytic residue at L123 (P = 0.0203);Gain of catalytic residue at L123 (P = 0.0203);Gain of catalytic residue at L123 (P = 0.0203);
MVP		0.90
MPC		0.011
ClinPred		0.36	T
GERP RS		-0.67
Varity_R		0.43
gMVP		0.061

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

Publications

LitVar

Other links and lift over

dbSNP: rs116880457; hg19: chr14-95081148;