Genetic Variant PRDM16:p.Ala658Thr (chr1-3412169-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022114.4(PRDM16):c.1972G>A(p.Ala658Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000049 in 1,428,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A658P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

PRDM16
NM_022114.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.80

Publications

1 publications found

Variant links:

Genes affected

PRDM16 (HGNC:14000): (PR/SET domain 16) The reciprocal translocation t(1;3)(p36;q21) occurs in a subset of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This gene is located near the 1p36.3 breakpoint and has been shown to be specifically expressed in the t(1:3)(p36,q21)-positive MDS/AML. The protein encoded by this gene is a zinc finger transcription factor and contains an N-terminal PR domain. The translocation results in the overexpression of a truncated version of this protein that lacks the PR domain, which may play an important role in the pathogenesis of MDS and AML. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

PRDM16 Gene-Disease associations (from GenCC):

left ventricular noncompaction 8
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

PRDM16 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06547946).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4 link	c.1972G>A	p.Ala658Thr	missense_variant	Exon 9 of 17	ENST00000270722.10	NP_071397.3	Q9HAZ2-1
PRDM16	NM_199454.3 link	c.1972G>A	p.Ala658Thr	missense_variant	Exon 9 of 17		NP_955533.2	Q9HAZ2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10 link	c.1972G>A	p.Ala658Thr	missense_variant	Exon 9 of 17	1	NM_022114.4	ENSP00000270722.5		Q9HAZ2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000879

AC:

AN:

227574

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000310

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000961

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000490

AC:

AN:

1428418

Hom.:

Cov.:

AF XY:

0.00000425

AC XY:

AN XY:

705728

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32636

American (AMR)

AF:

0.0000237

AC:

AN:

42182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24264

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39222

South Asian (SAS)

AF:

0.00

AC:

AN:

81910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.00000366

AC:

AN:

1092616

Other (OTH)

AF:

0.00

AC:

AN:

58814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.016

T;.;.;T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.76

T;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.065

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

.;L;.;L;.

PhyloP100

1.8

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

N;N;N;N;N

REVEL

Benign

0.059

Sift

Benign

0.15

T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.33, 0.0030

.;B;.;B;.

Vest4

0.074

MutPred

0.14

.;Gain of glycosylation at A658 (P = 0.0036);.;Gain of glycosylation at A658 (P = 0.0036);.;

MVP

0.20

MPC

0.36

ClinPred

0.077

GERP RS

1.8

Varity_R

0.041

gMVP

0.16

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over