Genetic Variant MAML3:p.Gln504_Gln509del (chr4-139889909-TTGCTGCTGCTGCTGCTGC-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_018717.5(MAML3):c.1509_1526delGCAGCAGCAGCAGCAGCA(p.Gln504_Gln509del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000461 in 1,476,644 control chromosomes in the GnomAD database, including 7 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00042 ( 7 hom. )

Consequence

MAML3
NM_018717.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.00

Publications

3 publications found

Variant links:

Genes affected

MAML3 (HGNC:16272): (mastermind like transcriptional coactivator 3) Enables transcription coactivator activity. Involved in Notch signaling pathway and positive regulation of transcription by RNA polymerase II. Located in nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

MAML3 links:

ENSG00000294637 (HGNC:):

ENSG00000294637 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_018717.5

BS2

High AC in GnomAd4 at 80 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018717.5. 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
	MAML3	NM_018717.5	MANE Select	c.1509_1526delGCAGCAGCAGCAGCAGCA	p.Gln504_Gln509del	disruptive_inframe_deletion	Exon 2 of 5	NP_061187.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAML3	ENST00000509479.6	TSL:1 MANE Select	c.1509_1526delGCAGCAGCAGCAGCAGCA	p.Gln504_Gln509del	disruptive_inframe_deletion	Exon 2 of 5	ENSP00000421180.1	Q96JK9
MAML3	ENST00000899537.1		c.1509_1526delGCAGCAGCAGCAGCAGCA	p.Gln504_Gln509del	disruptive_inframe_deletion	Exon 2 of 5	ENSP00000569596.1
MAML3	ENST00000502696.1	TSL:2	c.109-159260_109-159243delGCAGCAGCAGCAGCAGCA		intron	N/A	ENSP00000422783.1	H0Y920

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

AN:

47822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000598

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000747

Gnomad ASJ

AF:

0.0284

Gnomad EAS

AF:

0.00303

Gnomad SAS

AF:

0.00156

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0104

Gnomad NFE

AF:

0.00327

Gnomad OTH

AF:

0.00621

GnomAD4 exome

AF:

0.000421

AC:

601

AN:

1428734

Hom.:

AF XY:

0.000411

AC XY:

291

AN XY:

707948

show subpopulations

African (AFR)

AF:

0.000611

AC:

AN:

32736

American (AMR)

AF:

0.000522

AC:

AN:

44096

Ashkenazi Jewish (ASJ)

AF:

0.00483

AC:

123

AN:

25486

East Asian (EAS)

AF:

0.000592

AC:

AN:

38820

South Asian (SAS)

AF:

0.000469

AC:

AN:

85314

European-Finnish (FIN)

AF:

0.0000382

AC:

AN:

52410

Middle Eastern (MID)

AF:

0.00215

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.000272

AC:

295

AN:

1085326

Other (OTH)

AF:

0.00107

AC:

AN:

58958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00167

AC:

AN:

47910

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

AN XY:

23536

show subpopulations

African (AFR)

AF:

0.000596

AC:

AN:

28500

American (AMR)

AF:

0.000933

AC:

AN:

5358

Ashkenazi Jewish (ASJ)

AF:

0.0284

AC:

AN:

670

East Asian (EAS)

AF:

0.00303

AC:

AN:

2310

South Asian (SAS)

AF:

0.00156

AC:

AN:

1284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1668

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00341

AC:

AN:

7334

Other (OTH)

AF:

0.00617

AC:

AN:

648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.0

Mutation Taster

=165/35

disease causing (fs/PTC)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-139889909-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

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