NM_002701.6:c.74C>T

Variant names:

• chr6-31170547-G-A
• rs1264513957
• NM_002701.6:c.74C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_002701.6(POU5F1):​c.74C>T​(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000509 in 1,570,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POU5F1 NM_002701.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

Genes affected

POU5F1 (HGNC:9221): (POU class 5 homeobox 1) This gene encodes a transcription factor containing a POU homeodomain that plays a key role in embryonic development and stem cell pluripotency. Aberrant expression of this gene in adult tissues is associated with tumorigenesis. This gene can participate in a translocation with the Ewing's sarcoma gene on chromosome 21, which also leads to tumor formation. Alternative splicing, as well as usage of alternative AUG and non-AUG translation initiation codons, results in multiple isoforms. One of the AUG start codons is polymorphic in human populations. Related pseudogenes have been identified on chromosomes 1, 3, 8, 10, and 12. [provided by RefSeq, Oct 2013]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.099977314).
• BP6: Variant 6-31170547-G-A is Benign according to our data. Variant chr6-31170547-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3782083.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU5F1	NM_002701.6	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 5	ENST00000259915.13	NP_002692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU5F1	ENST00000259915.13	c.74C>T	p.Pro25Leu	missense_variant	Exon 1 of 5	1	NM_002701.6	ENSP00000259915.7
POU5F1	ENST00000461401.1	n.112C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
POU5F1	ENST00000441888.7	c.-183-4500C>T		intron_variant	Intron 1 of 4	1		ENSP00000389359.2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418222 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 701526

African (AFR) AF: 0.00 AC: 0 AN: 32488

American (AMR) AF: 0.00 AC: 0 AN: 38130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 37446

South Asian (SAS) AF: 0.00 AC: 0 AN: 81104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4762

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090566

Other (OTH) AF: 0.00 AC: 0 AN: 58684

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74470

African (AFR) AF: 0.000120 AC: 5 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 21, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.073
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.
PhyloP100		1.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.94	N;.
REVEL	Benign	0.080
Sift	Benign	0.22	T;.
Sift4G	Benign	0.72	T;.
Polyphen		0.0030	B;.
Vest4		0.18
MVP		0.35
MPC		0.42
ClinPred		0.58	D
GERP RS		2.9
PromoterAI		-0.026	Neutral
Varity_R		0.041
gMVP		0.16
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1264513957; hg19: chr6-31138324; COSMIC: COSV99463194; COSMIC: COSV99463194;