1-3411763-G-T

Position:

• chr1-3411763-G-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.1566G>T​(p.Leu522Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,611,606 control chromosomes in the GnomAD database, including 8 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. L522L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (7 hom.)
• Consequence: PRDM16 NM_022114.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.698

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=0.008493364).
• BP6: Variant 1-3411763-G-T is Benign according to our data. Variant chr1-3411763-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 474407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM16	NM_022114.4	c.1566G>T	p.Leu522Phe	missense_variant	9/17	ENST00000270722.10
PRDM16	NM_199454.3	c.1566G>T	p.Leu522Phe	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM16	ENST00000270722.10	c.1566G>T	p.Leu522Phe	missense_variant	9/17	1	NM_022114.4	P1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 151910 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

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: 0.00144

GnomAD3 exomes AF: 0.00184 AC: 453 AN: 246614 Hom.: 7 AF XY: 0.00139 AC XY: 187 AN XY: 134076

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000356 AC: 520 AN: 1459578 Hom.: 7 Cov.: 32 AF XY: 0.000296 AC XY: 215 AN XY: 726184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152028 Hom.: 1 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00308

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: 0.00142

Alfa AF: 0.0000101 Hom.: 0

Bravo AF: 0.000873

ExAC AF: 0.00139 AC: 168

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2017	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. -

Left ventricular noncompaction 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;.;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
MetaRNN	Benign	0.0085	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.044	D;D;D;D;D
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		1.0	.;D;.;D;.
Vest4		0.77
MutPred		0.22		.;Loss of glycosylation at S521 (P = 0.062);.;Loss of glycosylation at S521 (P = 0.062);.;
MVP		0.47
MPC		1.2
ClinPred		0.099	T
GERP RS		4.4
Varity_R		0.085
gMVP		0.24

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: rs554705536; hg19: chr1-3328327;