NM_014757.5:c.262C>A

Variant names:

• chr5-179733374-C-A
• rs1188277658
• NM_014757.5:c.262C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014757.5(MAML1):​c.262C>A​(p.Pro88Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000047 in 1,212,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P88A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: MAML1 NM_014757.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.145
• Publications: 1 publications found

Genes affected

MAML1 (HGNC:13632): (mastermind like transcriptional coactivator 1) This protein is the human homolog of mastermind, a Drosophila protein that plays a role in the Notch signaling pathway involved in cell-fate determination. There is in vitro evidence that the human homolog forms a complex with the intracellular portion of human Notch receptors and can increase expression of a Notch-induced gene. This evidence supports its proposed function as a transcriptional co-activator in the Notch signaling pathway. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1250298).
• BS2: High AC in GnomAdExome4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014757.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAML1	NM_014757.5	MANE Select	c.262C>A	p.Pro88Thr	missense	Exon 1 of 5	NP_055572.1	Q92585

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAML1	ENST00000292599.4	TSL:1 MANE Select	c.262C>A	p.Pro88Thr	missense	Exon 1 of 5	ENSP00000292599.3	Q92585
	MAML1	ENST00000933871.1		c.262C>A	p.Pro88Thr	missense	Exon 1 of 5	ENSP00000603930.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150332 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 56 AN: 1062332 Hom.: 0 Cov.: 30 AF XY: 0.0000509 AC XY: 26 AN XY: 510588

African (AFR) AF: 0.00 AC: 0 AN: 21102

American (AMR) AF: 0.00 AC: 0 AN: 6880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11968

East Asian (EAS) AF: 0.00 AC: 0 AN: 21962

South Asian (SAS) AF: 0.00 AC: 0 AN: 23888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2688

European-Non Finnish (NFE) AF: 0.0000569 AC: 52 AN: 913084

Other (OTH) AF: 0.0000975 AC: 4 AN: 41044

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150332 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73336

African (AFR) AF: 0.00 AC: 0 AN: 41232

American (AMR) AF: 0.00 AC: 0 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67468

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.73
DANN	Benign	0.61
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.14
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.044
Sift	Benign	0.22	T
Sift4G	Uncertain	0.026	D
Polyphen		0.34	B
Vest4		0.064
MutPred		0.11		Gain of phosphorylation at P88 (P = 0.0087)
MVP		0.35
MPC		1.9
ClinPred		0.10	T
GERP RS		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.030
gMVP		0.17
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1188277658; hg19: chr5-179160375;