chr14-94614679-A-T

Variant names:

• chr14-94614679-A-T
• rs778805359
• NM_001085.5:c.238A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001085.5(SERPINA3):​c.238A>T​(p.Ile80Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINA3 NM_001085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.532

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA3	NM_001085.5	c.238A>T	p.Ile80Phe	missense_variant	Exon 2 of 5	ENST00000393078.5	NP_001076.2
SERPINA3	NM_001384672.1	c.238A>T	p.Ile80Phe	missense_variant	Exon 2 of 5		NP_001371601.1
SERPINA3	NM_001384673.1	c.238A>T	p.Ile80Phe	missense_variant	Exon 3 of 6		NP_001371602.1
SERPINA3	NM_001384674.1	c.238A>T	p.Ile80Phe	missense_variant	Exon 3 of 6		NP_001371603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA3	ENST00000393078.5	c.238A>T	p.Ile80Phe	missense_variant	Exon 2 of 5	1	NM_001085.5	ENSP00000376793.3
ENSG00000273259	ENST00000553947.1	n.*1064A>T		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000452367.2
ENSG00000273259	ENST00000553947.1	n.*1064A>T		3_prime_UTR_variant	Exon 5 of 8	2		ENSP00000452367.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	3.6
DANN	Benign	0.97
DEOGEN2	Uncertain	0.64	D;D;.;D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.93	D;.;D;.
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.5	H;H;.;H
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.53
MutPred		0.66		Gain of catalytic residue at I80 (P = 0.0011);Gain of catalytic residue at I80 (P = 0.0011);Gain of catalytic residue at I80 (P = 0.0011);Gain of catalytic residue at I80 (P = 0.0011);
MVP		0.92
MPC		0.057
ClinPred		0.95	D
GERP RS		-2.3
Varity_R		0.59
gMVP		0.48

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: rs778805359; hg19: chr14-95081016;