chr16-23624093-A-T

Variant names:

• chr16-23624093-A-T
• rs763645981
• NM_024675.4:c.2750T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024675.4(PALB2):​c.2750T>A​(p.Val917Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000069 in 1,449,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V917A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Scores: Splicing: ADA: 0.6490
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

ENSG00000261723 (HGNC:58305):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PALB2	NM_024675.4	c.2750T>A	p.Val917Asp	missense_variant, splice_region_variant	Exon 8 of 13	ENST00000261584.9	NP_078951.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PALB2	ENST00000261584.9	c.2750T>A	p.Val917Asp	missense_variant, splice_region_variant	Exon 8 of 13	1	NM_024675.4	ENSP00000261584.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249522 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449812 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 722024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.84
MutPred		0.43		.;Loss of sheet (P = 0.0483);
MVP		0.74
MPC		0.41
ClinPred		0.94	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.65
dbscSNV1_RF	Benign	0.59
SpliceAI score (max)		0.050		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: rs763645981; hg19: chr16-23635414; COSMIC: COSV55162954; COSMIC: COSV55162954;