rs1328062930

Variant names:

• chr11-64810039-G-A
• rs1328062930
• NM_001370259.2:c.71C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.
• BP6: Variant 11-64810039-G-A is Benign according to our data. Variant chr11-64810039-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 527250.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.71C>T	p.Ala24Val	missense_variant	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.71C>T	p.Ala24Val	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

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: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:1 Benign:1

Jan 18, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.;.;.
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;