Variant 2-104855706-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM5BP4_StrongBP6_ModerateBS2

The NM_006236.3(POU3F3):c.196G>A(p.Asp66Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000805 in 1,241,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D66?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

POU3F3
NM_006236.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.951

Variant links:

Genes affected

POU3F3 (HGNC:9216): (POU class 3 homeobox 3) This gene encodes a POU-domain containing protein that functions as a transcription factor. The encoded protein recognizes an octamer sequence in the DNA of target genes. This protein may play a role in development of the nervous system. [provided by RefSeq, Apr 2015]

POU3F3 links:

ENSG00000269707 (HGNC:):

ENSG00000269707 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-104855705-GGA-GT is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.018398464).

BP6

Variant 2-104855706-G-A is Benign according to our data. Variant chr2-104855706-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3216929.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU3F3	NM_006236.3 linkuse as main transcript	c.196G>A	p.Asp66Asn	missense_variant	1/1	ENST00000361360.4	NP_006227.1	P20264

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU3F3	ENST00000361360.4 linkuse as main transcript	c.196G>A	p.Asp66Asn	missense_variant	1/1	6	NM_006236.3	ENSP00000355001.2		P20264

Frequencies

GnomAD3 genomes

AF:

0.000103

AC:

AN:

145634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00118

Gnomad EAS

AF:

0.000202

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000457

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

156536

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

90622

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00147

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.000587

GnomAD4 exome

AF:

0.0000776

AC:

AN:

1096000

Hom.:

Cov.:

AF XY:

0.0000848

AC XY:

AN XY:

542772

show subpopulations

Gnomad4 AFR exome

AF:

0.0000465

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00228

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000410

Gnomad4 OTH exome

AF:

0.000236

GnomAD4 genome

AF:

0.000103

AC:

AN:

145736

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

70870

show subpopulations

Gnomad4 AFR

AF:

0.000172

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00118

Gnomad4 EAS

AF:

0.000203

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000457

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.092

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.24

REVEL

Benign

0.27

Sift

Benign

0.58

Sift4G

Benign

0.55

Polyphen

0.52

Vest4

0.069

MutPred

0.21

Gain of MoRF binding (P = 0.0321);

MVP

0.39

ClinPred

0.0056

GERP RS

1.1

Varity_R

0.086

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over