rs1114167495

Variant names:

• chr11-64806331-T-C
• rs1114167495
• NM_001370259.2:c.950A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001370259.2(MEN1):​c.950A>G​(p.His317Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H317Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.09

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64806332-G-A is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-64806331-T-C is Pathogenic according to our data. Variant chr11-64806331-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428033.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-64806331-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.950A>G	p.His317Arg	missense_variant	Exon 7 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.950A>G	p.His317Arg	missense_variant	Exon 7 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 09, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H317R variant (also known as c.950A>G), located in coding exon 6 of the MEN1 gene, results from an A to G substitution at nucleotide position 950. The histidine at codon 317 is replaced by arginine, an amino acid with highly similar properties. This alteration was observed in a proband suspected of having MEN1 with a history of hyperparathyroidism and a carcinoid tumor (Roijers, JF et al. Eur J Clin Invest. 2000 Jun;30(6):487-92). This mutation was also identified in a MEN1 family with at least two affected individuals with a history of primary hyperparathyroidism and/or carcinoid tumors (Wautot, V et al. Hum Mutat. 2002 Jul;20(1):35-47). Of note, this alteration is also designated as c.1060A>G in published literature. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;D;D;D;D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;.;D;.;.;D;.;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;M;M;M;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;.
Polyphen		0.97, 1.0, 1.0	.;D;D;D;D;D;D;D;D;.
Vest4		0.88
MutPred		0.96		.;.;.;.;.;Gain of MoRF binding (P = 0.0691);Gain of MoRF binding (P = 0.0691);Gain of MoRF binding (P = 0.0691);Gain of MoRF binding (P = 0.0691);.;
MVP		0.99
MPC		2.0
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1114167495; hg19: chr11-64573803;