rs1328062930

Positions:

• chr11-64810039-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001370259.2(MEN1):​c.71C>T​(p.Ala24Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.21

Genes affected

MEN1 (HGNC:7010): (menin 1) This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.71C>T	p.Ala24Val	missense_variant	2/10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.71C>T	p.Ala24Val	missense_variant	2/10	5	NM_001370259.2	ENSP00000394933	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457322 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724496

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 24 of the MEN1 protein (p.Ala24Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 527250). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MEN1 protein function. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2023

The p.A24V variant (also known as c.71C>T), located in coding exon 1 of the MEN1 gene, results from a C to T substitution at nucleotide position 71. The alanine at codon 24 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;.;D;D;D;D;D;.;D;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	.;N;N;N;N;N;N;N;N;.;.;.;.;.
MutationTaster	Benign	0.61	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.047	D;D;D;D;D;D;D;D;D;D;D;D;T;T
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D;D;.;D;D;.;.
Polyphen		0.53, 0.93, 0.94	.;P;P;P;P;P;P;P;P;.;.;.;.;.
Vest4		0.26
MutPred		0.46		Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);Loss of disorder (P = 0.128);
MVP		0.86
MPC		1.2
ClinPred		0.62	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.37

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: rs1328062930; hg19: chr11-64577511;