11-95979394-A-G

Variant names:

• chr11-95979394-A-G
• NM_032427.4:c.3025T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032427.4(MAML2):​c.3025T>C​(p.Phe1009Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAML2 NM_032427.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.70

Genes affected

MAML2 (HGNC:16259): (mastermind like transcriptional coactivator 2) The protein encoded by this gene is a member of the Mastermind-like family of proteins. All family members are proline and glutamine-rich, and contain a conserved basic domain that binds the ankyrin repeat domain of the intracellular domain of the Notch receptors (ICN1-4) in their N-terminus, and a transcriptional activation domain in their C-terminus. This protein binds to an extended groove that is formed by the interaction of CBF1, Suppressor of Hairless, LAG-1 (CSL) with ICN, and positively regulates Notch signaling. High levels of expression of this gene have been observed in several B cell-derived lymphomas. Translocations resulting in fusion proteins with both CRTC1 and CRTC3 have been implicated in the development of mucoepidermoid carcinomas, while a translocation event with CXCR4 has been linked with chronic lymphocytic leukemia (CLL). Copy number variation in the polyglutamine tract has been observed. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAML2	NM_032427.4	c.3025T>C	p.Phe1009Leu	missense_variant	Exon 5 of 5	ENST00000524717.6	NP_115803.1
MAML2	XM_011543023.4	c.2584T>C	p.Phe862Leu	missense_variant	Exon 5 of 5		XP_011541325.1
MAML2	XM_047427710.1	c.2341T>C	p.Phe781Leu	missense_variant	Exon 5 of 5		XP_047283666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAML2	ENST00000524717.6	c.3025T>C	p.Phe1009Leu	missense_variant	Exon 5 of 5	1	NM_032427.4	ENSP00000434552.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461356 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726918

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0080	D;.
Sift4G	Benign	0.64	T;T
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.29		Loss of catalytic residue at F1009 (P = 0.0411);.;
MVP		0.58
MPC		0.070
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-95712558;