rs188908415

chr1-3411623-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022114.4(PRDM16):c.1426C>T(p.Pro476Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,613,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.10

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054835975).
• BP6: Variant 1-3411623-C-T is Benign according to our data. Variant chr1-3411623-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3411623-C-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.1426C>T	p.Pro476Ser	missense_variant	9/17	ENST00000270722.10
PRDM16	NM_199454.3	c.1426C>T	p.Pro476Ser	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.1426C>T	p.Pro476Ser	missense_variant	9/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152180 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000955

GnomAD3 exomes AF: 0.000338 AC: 84 AN: 248366 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 134852

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000122 AC: 179 AN: 1461664 Hom.: 0 Cov.: 32 AF XY: 0.0000935 AC XY: 68 AN XY: 727120

Gnomad4 AFR exome AF: 0.00484

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152298 Hom.: 2 Cov.: 33 AF XY: 0.00111 AC XY: 83 AN XY: 74458

Gnomad4 AFR AF: 0.00436

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.00148

ESP6500AA AF: 0.00446 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000421 AC: 51

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PRDM16: BP4, BS1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Pro476Ser in exon 9 of PRDM16: This variant is not expected to have clinical sig nificance because it has been identified in 3.4% (6/176) of Yoruba (Nigerian) ch romosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.n lm.nih.gov/projects/SNP; dbSNP rs188908415). -

PRDM16-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Left ventricular noncompaction 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.;.;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0055	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		1.0, 0.96	.;D;.;D;.
Vest4		0.19
MVP		0.56
MPC		0.38
ClinPred		0.029	T
GERP RS		5.2
Varity_R		0.051
gMVP		0.32

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: rs188908415; hg19: chr1-3328187;