chr11-64805036-G-C

Position:

• chr11-64805036-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_001370259.2(MEN1):​c.1348C>G​(p.Gln450Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q450H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 NM_001370259.2 missense, splice_region
• Scores: Splicing: ADA: 0.1073
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.39

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-64805034-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 818932.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
• PP2: Missense variant where missense usually causes diseases, MEN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.31329143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.1348C>G	p.Gln450Glu	missense_variant, splice_region_variant	9/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.1348C>G	p.Gln450Glu	missense_variant, splice_region_variant	9/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Benign	0.92
Eigen	Benign	-0.093
Eigen_PC	Benign	0.040
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;.;D;.;.;D;.
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.25	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.57	T;T;T;T;T;T;T;T
Sift4G	Benign	0.79	T;T;T;T;T;T;T;T
Polyphen		0.50	P;B;B;B;B;B;B;B
Vest4		0.47
MutPred		0.64		.;.;.;.;Gain of ubiquitination at K459 (P = 0.0457);Gain of ubiquitination at K459 (P = 0.0457);Gain of ubiquitination at K459 (P = 0.0457);Gain of ubiquitination at K459 (P = 0.0457);
MVP		0.87
MPC		1.1
ClinPred		0.77	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64572508;