5-179733353-A-G

Variant names:

• chr5-179733353-A-G
• rs1181039293
• NM_014757.5:c.241A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014757.5(MAML1):​c.241A>G​(p.Thr81Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000885 in 1,129,522 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. 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. T81P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: MAML1 NM_014757.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069107115).

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.241A>G	p.Thr81Ala	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.241A>G	p.Thr81Ala	missense	Exon 1 of 5	ENSP00000292599.3	Q92585
	MAML1	ENST00000933871.1		c.241A>G	p.Thr81Ala	missense	Exon 1 of 5	ENSP00000603930.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.85e-7 AC: 1 AN: 1129522 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 550174

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22560

American (AMR) AF: 0.00 AC: 0 AN: 13658

Ashkenazi Jewish (ASJ) AF: 0.0000660 AC: 1 AN: 15146

East Asian (EAS) AF: 0.00 AC: 0 AN: 22896

South Asian (SAS) AF: 0.00 AC: 0 AN: 41730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3000

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 942786

Other (OTH) AF: 0.00 AC: 0 AN: 43960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.013
DANN	Benign	0.20
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0027	N
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.53
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.20	N
REVEL	Benign	0.0080
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.26		Loss of glycosylation at T81 (P = 0.0015)
MVP		0.42
MPC		1.7
ClinPred		0.068	T
GERP RS		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.28
Mutation Taster		=96/4	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: rs1181039293; hg19: chr5-179160354;