rs374271999

Variant names:

• chr1-3412705-C-T
• rs374271999
• NM_022114.4:c.2508C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-3412705-C-T
• chr1-3412705-C-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_022114.4(PRDM16):​c.2508C>T​(p.Gly836Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,495,928 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (5 hom.)
• Consequence: PRDM16 NM_022114.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.441
• Publications: 1 publications found

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):

• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• left ventricular noncompaction 8

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-3412705-C-T is Benign according to our data. Variant chr1-3412705-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 449703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.441 with no splicing effect.
• BS2: High AC in GnomAd4 at 53 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022114.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	NM_022114.4	MANE Select	c.2508C>T	p.Gly836Gly	synonymous	Exon 9 of 17	NP_071397.3
	PRDM16	NM_199454.3		c.2508C>T	p.Gly836Gly	synonymous	Exon 9 of 17	NP_955533.2	Q9HAZ2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM16	ENST00000270722.10	TSL:1 MANE Select	c.2508C>T	p.Gly836Gly	synonymous	Exon 9 of 17	ENSP00000270722.5	Q9HAZ2-1
	PRDM16	ENST00000378391.6	TSL:1	c.2508C>T	p.Gly836Gly	synonymous	Exon 9 of 17	ENSP00000367643.2	Q9HAZ2-2
	PRDM16	ENST00000512462.5	TSL:1	n.2286C>T		non_coding_transcript_exon	Exon 8 of 16

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000685 AC: 71 AN: 103720 AF XY: 0.000774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000231

Gnomad FIN exome AF: 0.000191

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.000373 AC: 501 AN: 1343636 Hom.: 5 Cov.: 35 AF XY: 0.000445 AC XY: 293 AN XY: 657868

African (AFR) AF: 0.0000680 AC: 2 AN: 29408

American (AMR) AF: 0.000257 AC: 7 AN: 27246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21790

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34962

South Asian (SAS) AF: 0.00105 AC: 75 AN: 71206

European-Finnish (FIN) AF: 0.000206 AC: 9 AN: 43754

Middle Eastern (MID) AF: 0.00241 AC: 13 AN: 5398

European-Non Finnish (NFE) AF: 0.000345 AC: 364 AN: 1054452

Other (OTH) AF: 0.000541 AC: 30 AN: 55420

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74468

African (AFR) AF: 0.000192 AC: 8 AN: 41570

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.000363

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Left ventricular noncompaction 8 (1)
-	-	1	not specified (1)
-	-	1	PRDM16-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.56
DANN	Benign	0.71
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs374271999; hg19: chr1-3329269;