rs200169663

Positions:

• chr1-3405596-C-G
• chr1-3405596-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000270722.10(PRDM16):​c.1134C>G​(p.Ser378=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,611,430 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S378S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00061 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (3 hom.)
• Consequence: PRDM16 ENST00000270722.10 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.415

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 1-3405596-C-G is Benign according to our data. Variant chr1-3405596-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 227859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3405596-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.415 with no splicing effect.
• BS2: High AC in GnomAd4 at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.1134C>G	p.Ser378=	synonymous_variant	8/17	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.1134C>G	p.Ser378=	synonymous_variant	8/17		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.1134C>G	p.Ser378=	synonymous_variant	8/17	1	NM_022114.4	ENSP00000270722	P1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000876 AC: 216 AN: 246480 Hom.: 1 AF XY: 0.000805 AC XY: 108 AN XY: 134158

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0178

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000243

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.000495 AC: 722 AN: 1459216 Hom.: 3 Cov.: 31 AF XY: 0.000488 AC XY: 354 AN XY: 725924

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000954

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152214 Hom.: 1 Cov.: 33 AF XY: 0.000619 AC XY: 46 AN XY: 74358

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00199 Hom.: 1

Bravo AF: 0.000529

EpiCase AF: 0.000164

EpiControl AF: 0.000476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	p.Ser378Ser in exon 8 of PRDM16: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.1% (7/8590) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	This variant is associated with the following publications: (PMID: 21750719) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PRDM16: BP4, BP7 -

Left ventricular noncompaction 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.5
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200169663; hg19: chr1-3322160; COSMIC: COSV54597490;