Genetic Variant PNMA8A:p.Cys295Tyr (chr19-46470152-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018215.4(PNMA8A):c.884G>A(p.Cys295Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,640 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000086 ( 1 hom. )

Consequence

PNMA8A
NM_018215.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.525

Publications

0 publications found

Variant links:

Genes affected

PNMA8A (HGNC:25578): (PNMA family member 8A)

PNMA8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006021023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNMA8A	NM_018215.4 link	c.884G>A	p.Cys295Tyr	missense_variant	Exon 2 of 3	ENST00000313683.15	NP_060685.2	Q86V59-1
PNMA8A	NM_001103149.2 link	c.884G>A	p.Cys295Tyr	missense_variant	Exon 2 of 3		NP_001096619.1	Q86V59-2
PNMA8A	XM_011527067.3 link	c.884G>A	p.Cys295Tyr	missense_variant	Exon 2 of 3		XP_011525369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNMA8A	ENST00000313683.15 link	c.884G>A	p.Cys295Tyr	missense_variant	Exon 2 of 3	1	NM_018215.4	ENSP00000318131.10	Q86V59-1
PNMA8A	ENST00000438932.2 link	c.884G>A	p.Cys295Tyr	missense_variant	Exon 2 of 3	1		ENSP00000410273.1	Q86V59-2
PNMA8A	ENST00000602246.1 link	c.216+668G>A		intron_variant	Intron 2 of 2	4		ENSP00000473064.1	M0R388

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000183

AC:

AN:

250914

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461298

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

726932

show subpopulations

African (AFR)

AF:

0.00284

AC:

AN:

33438

American (AMR)

AF:

0.000403

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111798

Other (OTH)

AF:

0.000199

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152342

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41582

American (AMR)

AF:

0.000588

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.000929

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.884G>A (p.C295Y) alteration is located in exon 2 (coding exon 1) of the PNMAL1 gene. This alteration results from a G to A substitution at nucleotide position 884, causing the cysteine (C) at amino acid position 295 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.2

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.0062

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.45

T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-0.98

PhyloP100

-0.53

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.089

Sift

Benign

0.030

D;D

Sift4G

Benign

0.54

T;T

Polyphen

0.22

B;B

Vest4

0.28

MVP

0.12

MPC

0.43

ClinPred

0.025

GERP RS

-5.7

Varity_R

0.090

gMVP

0.013

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over