4-15971072-G-T

Position:

• chr4-15971072-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_006017.3(PROM1):​c.2593C>A​(p.His865Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PROM1 NM_006017.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.683

Genes affected

PROM1 (HGNC:9454): (prominin 1) This gene encodes a pentaspan transmembrane glycoprotein. The protein localizes to membrane protrusions and is often expressed on adult stem cells, where it is thought to function in maintaining stem cell properties by suppressing differentiation. Mutations in this gene have been shown to result in retinitis pigmentosa and Stargardt disease. Expression of this gene is also associated with several types of cancer. This gene is expressed from at least five alternative promoters that are expressed in a tissue-dependent manner. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 51) in uniprot entity PROM1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006017.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03813663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROM1	NM_006017.3	c.2593C>A	p.His865Asn	missense_variant	27/28	ENST00000447510.7	NP_006008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROM1	ENST00000447510.7	c.2593C>A	p.His865Asn	missense_variant	27/28	1	NM_006017.3	ENSP00000415481.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426400 Hom.: 0 Cov.: 29 AF XY: 0.00000283 AC XY: 2 AN XY: 706762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000493

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: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 15, 2021

This sequence change replaces histidine with asparagine at codon 865 of the PROM1 protein (p.His865Asn). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PROM1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.1
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T;.;.;.;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.44	T;T;T;.;T;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.038	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.;.;L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.17	N;N;N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.24	T;T;T;T;T;T
Sift4G	Benign	0.33	T;.;.;T;T;T
Polyphen		0.44	B;B;B;B;B;B
Vest4		0.18
MutPred		0.20		Loss of catalytic residue at H865 (P = 0.0628);.;.;.;.;Loss of catalytic residue at H865 (P = 0.0628);
MVP		0.014
MPC		0.019
ClinPred		0.078	T
GERP RS		-0.28
Varity_R		0.026
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs748272325; hg19: chr4-15972695;