Genetic Variant MAML1:p.Thr110Thr (chr5-179765340-A-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_014757.5(MAML1):c.330A>G(p.Thr110Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0071 in 1,596,726 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 50 hom. )

Consequence

MAML1
NM_014757.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.36

Publications

4 publications found

Variant links:

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]

MAML1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 5-179765340-A-G is Benign according to our data. Variant chr5-179765340-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2656134.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.36 with no splicing effect.

BS2

High AC in GnomAd4 at 731 AD gene.

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.330A>G	p.Thr110Thr	synonymous	Exon 2 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.330A>G	p.Thr110Thr	synonymous	Exon 2 of 5	ENSP00000292599.3	Q92585
	MAML1	ENST00000933871.1		c.330A>G	p.Thr110Thr	synonymous	Exon 2 of 5	ENSP00000603930.1

Frequencies

GnomAD3 genomes

AF:

0.00480

AC:

731

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00869

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00426

AC:

1011

AN:

237142

AF XY:

0.00433

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.00206

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00133

Gnomad NFE exome

AF:

0.00762

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00734

AC:

10604

AN:

1444376

Hom.:

Cov.:

AF XY:

0.00703

AC XY:

5050

AN XY:

718180

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

32392

American (AMR)

AF:

0.00184

AC:

AN:

40138

Ashkenazi Jewish (ASJ)

AF:

0.00261

AC:

AN:

24890

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.000728

AC:

AN:

83830

European-Finnish (FIN)

AF:

0.00190

AC:

101

AN:

53056

Middle Eastern (MID)

AF:

0.000705

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00897

AC:

9916

AN:

1105252

Other (OTH)

AF:

0.00581

AC:

346

AN:

59572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

475

950

1425

1900

2375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

396

792

1188

1584

1980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00480

AC:

731

AN:

152350

Hom.:

Cov.:

AF XY:

0.00436

AC XY:

325

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41588

American (AMR)

AF:

0.00242

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00869

AC:

591

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00625

Hom.:

Bravo

AF:

0.00447

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.44

(source)

DANN

Benign

0.62

PhyloP100

-1.4

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over