5-179765333-A-G

Position:

• chr5-179765333-A-G

Variant summary

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

The NM_014757.5(MAML1):​c.323A>G​(p.His108Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAML1 NM_014757.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.85

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

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/exons	MANE	Protein	UniProt
MAML1	NM_014757.5	c.323A>G	p.His108Arg	missense_variant	2/5	ENST00000292599.4	NP_055572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAML1	ENST00000292599.4	c.323A>G	p.His108Arg	missense_variant	2/5	1	NM_014757.5	ENSP00000292599.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2024

The c.323A>G (p.H108R) alteration is located in exon 2 (coding exon 2) of the MAML1 gene. This alteration results from a A to G substitution at nucleotide position 323, causing the histidine (H) at amino acid position 108 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Uncertain	0.019	D
Sift4G	Benign	0.17	T
Polyphen		0.97	D
Vest4		0.76
MutPred		0.16		Gain of MoRF binding (P = 0.0186);
MVP		0.43
MPC		0.48
ClinPred		0.87	D
GERP RS		3.6
Varity_R		0.073
gMVP		0.29

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: chr5-179192334;