NM_014757.5:c.289G>C

Variant names:

• chr5-179733401-G-C
• rs61751563
• NM_014757.5:c.289G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014757.5(MAML1):​c.289G>C​(p.Gly97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 1,151,656 control chromosomes in the GnomAD database, including 1,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (172 hom., cov: 33)
  • Exomes 𝑓: 0.048 (1182 hom.)
• Consequence: MAML1 NM_014757.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.20
• Publications: 5 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027258992).
• BP6: Variant 5-179733401-G-C is Benign according to our data. Variant chr5-179733401-G-C is described in ClinVar as Benign. ClinVar VariationId is 769312.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

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.289G>C	p.Gly97Arg	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.289G>C	p.Gly97Arg	missense	Exon 1 of 5	ENSP00000292599.3	Q92585
	MAML1	ENST00000933871.1		c.289G>C	p.Gly97Arg	missense	Exon 1 of 5	ENSP00000603930.1

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5762 AN: 150910 Hom.: 172 Cov.: 33

Gnomad AFR AF: 0.00908

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0624

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0528

Gnomad OTH AF: 0.0488

GnomAD2 exomes AF: 0.0179 AC: 1 AN: 56 AF XY: 0.0385

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0479 AC: 47924 AN: 1000638 Hom.: 1182 Cov.: 30 AF XY: 0.0483 AC XY: 23003 AN XY: 476732

African (AFR) AF: 0.00626 AC: 123 AN: 19640

American (AMR) AF: 0.0280 AC: 154 AN: 5502

Ashkenazi Jewish (ASJ) AF: 0.0865 AC: 871 AN: 10068

East Asian (EAS) AF: 0.000238 AC: 4 AN: 16782

South Asian (SAS) AF: 0.0187 AC: 361 AN: 19314

European-Finnish (FIN) AF: 0.0566 AC: 885 AN: 15634

Middle Eastern (MID) AF: 0.0715 AC: 174 AN: 2432

European-Non Finnish (NFE) AF: 0.0498 AC: 43516 AN: 873866

Other (OTH) AF: 0.0491 AC: 1836 AN: 37400

GnomAD4 genome AF: 0.0382 AC: 5763 AN: 151018 Hom.: 172 Cov.: 33 AF XY: 0.0386 AC XY: 2847 AN XY: 73808

African (AFR) AF: 0.00905 AC: 375 AN: 41420

American (AMR) AF: 0.0361 AC: 548 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 299 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4826

European-Finnish (FIN) AF: 0.0624 AC: 626 AN: 10028

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0528 AC: 3570 AN: 67648

Other (OTH) AF: 0.0488 AC: 102 AN: 2090

Alfa AF: 0.0456 Hom.: 24

Bravo AF: 0.0353

TwinsUK AF: 0.0529 AC: 196

ALSPAC AF: 0.0451 AC: 174

ExAC AF: 0.00369 AC: 155

Asia WGS AF: 0.0120 AC: 42 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.15	N
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.027
Sift	Uncertain	0.015	D
Sift4G	Benign	0.12	T
Polyphen		0.0070	B
Vest4		0.16
MPC		2.1
ClinPred		0.27	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.28
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: rs61751563; hg19: chr5-179160402; COSMIC: COSV52984946; COSMIC: COSV52984946;