5-179774846-G-A

Position:

• chr5-179774846-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014757.5(MAML1):​c.3020G>A​(p.Ser1007Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,611,242 control chromosomes in the GnomAD database, including 86,293 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.28 (6502 hom., cov: 34)
  • Exomes 𝑓: 0.33 (79791 hom.)
• Consequence: MAML1 NM_014757.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026194751).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAML1	NM_014757.5	c.3020G>A	p.Ser1007Asn	missense_variant	5/5	ENST00000292599.4	NP_055572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAML1	ENST00000292599.4	c.3020G>A	p.Ser1007Asn	missense_variant	5/5	1	NM_014757.5	ENSP00000292599.3

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43240 AN: 152138 Hom.: 6497 Cov.: 34

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.279 AC: 69791 AN: 249828 Hom.: 10583 AF XY: 0.281 AC XY: 37969 AN XY: 135116

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.206

Gnomad FIN exome AF: 0.356

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.325 AC: 474418 AN: 1458986 Hom.: 79791 Cov.: 40 AF XY: 0.322 AC XY: 233234 AN XY: 725268

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.356

Gnomad4 NFE exome AF: 0.349

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.284 AC: 43277 AN: 152256 Hom.: 6502 Cov.: 34 AF XY: 0.281 AC XY: 20910 AN XY: 74438

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.343

Gnomad4 OTH AF: 0.288

Alfa AF: 0.319 Hom.: 19652

Bravo AF: 0.271

TwinsUK AF: 0.352 AC: 1307

ALSPAC AF: 0.351 AC: 1352

ESP6500AA AF: 0.222 AC: 977

ESP6500EA AF: 0.340 AC: 2925

ExAC AF: 0.281 AC: 34119

Asia WGS AF: 0.189 AC: 656 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.21
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.27	N
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.1	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.066
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.11
ClinPred		0.00028	T
GERP RS		1.6
Varity_R		0.034
gMVP		0.042

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: rs6895902; hg19: chr5-179201847; COSMIC: COSV52982923; COSMIC: COSV52982923;