1-3425762-G-C

Variant names:

• chr1-3425762-G-C
• rs200643126
• NM_022114.4:c.3109+12G>C

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.3109+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,612,952 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: PRDM16 NM_022114.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.82

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 (BayesDel_noAF=-0.89).
• BP6: Variant 1-3425762-G-C is Benign according to our data. Variant chr1-3425762-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-3425762-G-C is described in Lovd as [Benign]. Variant chr1-3425762-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 290 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM16	NM_022114.4	c.3109+12G>C		intron_variant	Intron 13 of 16	ENST00000270722.10	NP_071397.3
PRDM16	NM_199454.3	c.3109+12G>C		intron_variant	Intron 13 of 16		NP_955533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM16	ENST00000270722.10	c.3109+12G>C		intron_variant	Intron 13 of 16	1	NM_022114.4	ENSP00000270722.5

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00179 AC: 442 AN: 247522 Hom.: 0 AF XY: 0.00181 AC XY: 244 AN XY: 134584

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00196 AC: 2862 AN: 1460688 Hom.: 4 Cov.: 32 AF XY: 0.00200 AC XY: 1452 AN XY: 726674

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00560

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00190 AC: 290 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74444

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 08, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.3109+12G>C in intron 13 of PRDM16: This variant is not expected to have clinic al significance because it is not located within the conserved splice consensus sequence. It has been identified in 0.5% (30/6582) of Finnish chromosomes and 0. 3% (170/65290) of European chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org/; dbSNP rs200643126). -

Feb 22, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction 8 Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.37
DANN	Benign	0.28

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: rs200643126; hg19: chr1-3342326;