13-78601969-C-A

Position:

• chr13-78601969-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006237.4(POU4F1):​c.706G>T​(p.Ala236Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,118,008 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: POU4F1 NM_006237.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.485

Genes affected

POU4F1 (HGNC:9218): (POU class 4 homeobox 1) This gene encodes a member of the POU-IV class of neural transcription factors. This protein is expressed in a subset of retinal ganglion cells and may be involved in the developing sensory nervous system. This protein may also promote the growth of cervical tumors. A translocation of this gene is associated with some adult acute myeloid leukemias. [provided by RefSeq, Mar 2012]

POU4F1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005672723).
• BP6: Variant 13-78601969-C-A is Benign according to our data. Variant chr13-78601969-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1694707.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd4 at 339 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU4F1	NM_006237.4	c.706G>T	p.Ala236Ser	missense_variant	2/2	ENST00000377208.7	NP_006228.3
POU4F1	XR_007063683.1	n.1186G>T		non_coding_transcript_exon_variant	1/2
OBI1-AS1	NR_047001.1	n.385-3332C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU4F1	ENST00000377208.7	c.706G>T	p.Ala236Ser	missense_variant	2/2	1	NM_006237.4	ENSP00000366413.4

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 339 AN: 146386 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000539

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.000829

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00498

GnomAD3 exomes AF: 0.00512 AC: 3 AN: 586 Hom.: 0 AF XY: 0.00311 AC XY: 1 AN XY: 322

Gnomad AFR exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00391

Gnomad OTH exome AF: 0.0714

GnomAD4 exome AF: 0.00255 AC: 2482 AN: 971516 Hom.: 6 Cov.: 20 AF XY: 0.00259 AC XY: 1186 AN XY: 457608

Gnomad4 AFR exome AF: 0.000573

Gnomad4 AMR exome AF: 0.00351

Gnomad4 ASJ exome AF: 0.00171

Gnomad4 EAS exome AF: 0.000119

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.000940

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00231 AC: 339 AN: 146492 Hom.: 3 Cov.: 30 AF XY: 0.00216 AC XY: 154 AN XY: 71342

Gnomad4 AFR AF: 0.000538

Gnomad4 AMR AF: 0.00169

Gnomad4 ASJ AF: 0.00207

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00728

Gnomad4 FIN AF: 0.000829

Gnomad4 NFE AF: 0.00275

Gnomad4 OTH AF: 0.00492

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00233

ExAC AF: 0.00530 AC: 10

Asia WGS AF: 0.00322 AC: 10 AN: 3118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.706G>T (p.A236S) alteration is located in exon 2 (coding exon 2) of the POU4F1 gene. This alteration results from a G to T substitution at nucleotide position 706, causing the alanine (A) at amino acid position 236 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

POU4F1: BS1, BS2 -

POU4F1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.20
Sift	Benign	0.19	T
Sift4G	Benign	0.36	T
Polyphen		0.44	B
Vest4		0.17
MVP		0.41
ClinPred		0.017	T
GERP RS		2.1
Varity_R		0.060
gMVP		0.35

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: rs754365572; hg19: chr13-79176104;