5-179733401-G-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAML1	NM_014757.5	c.289G>C	p.Gly97Arg	missense_variant	1/5	ENST00000292599.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAML1	ENST00000292599.4	c.289G>C	p.Gly97Arg	missense_variant	1/5	1	NM_014757.5	P1

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

GnomAD3 exomes AF: 0.0179 AC: 1 AN: 56 Hom.: 0 AF XY: 0.0385 AC XY: 1 AN XY: 26

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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

Gnomad4 AFR exome AF: 0.00626

Gnomad4 AMR exome AF: 0.0280

Gnomad4 ASJ exome AF: 0.0865

Gnomad4 EAS exome AF: 0.000238

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.0566

Gnomad4 NFE exome AF: 0.0498

Gnomad4 OTH exome AF: 0.0491

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

Gnomad4 AFR AF: 0.00905

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.0866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.0624

Gnomad4 NFE AF: 0.0528

Gnomad4 OTH AF: 0.0488

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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

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

LitVar

Other links and lift over

dbSNP: rs61751563; hg19: chr5-179160402; COSMIC: COSV52984946; COSMIC: COSV52984946;