Genetic Variant MAML3:p.Gln505_Gln509dup (chr4-139889909-T-TTGCTGCTGCTGCTGC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_018717.5(MAML3):c.1512_1526dupGCAGCAGCAGCAGCA(p.Gln505_Gln509dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000084 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MAML3
NM_018717.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.616

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 -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_018717.5

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.1512_1526dupGCAGCAGCAGCAGCA	p.Gln505_Gln509dup	disruptive_inframe_insertion	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.1512_1526dupGCAGCAGCAGCAGCA	p.Gln505_Gln509dup	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000421180.1	Q96JK9
MAML3	ENST00000899537.1		c.1512_1526dupGCAGCAGCAGCAGCA	p.Gln505_Gln509dup	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000569596.1
MAML3	ENST00000502696.1	TSL:2	c.109-159257_109-159243dupGCAGCAGCAGCAGCA		intron	N/A	ENSP00000422783.1	H0Y920

Frequencies

GnomAD3 genomes

AF:

0.0000836

AC:

AN:

47822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000780

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000273

Gnomad OTH

AF:

0.00155

GnomAD4 exome

AF:

0.0000189

AC:

AN:

1428740

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

707954

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32738

American (AMR)

AF:

0.0000227

AC:

AN:

44096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25486

East Asian (EAS)

AF:

0.000206

AC:

AN:

38818

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52410

Middle Eastern (MID)

AF:

0.000358

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.0000120

AC:

AN:

1085330

Other (OTH)

AF:

0.0000339

AC:

AN:

58958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.329

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000836

AC:

AN:

47822

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

AN XY:

23456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28408

American (AMR)

AF:

0.00

AC:

AN:

5354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

670

East Asian (EAS)

AF:

0.00

AC:

AN:

2312

South Asian (SAS)

AF:

0.000780

AC:

AN:

1282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000273

AC:

AN:

7336

Other (OTH)

AF:

0.00155

AC:

AN:

644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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

0.62

Mutation Taster

=78/22

polymorphism

(source)

Splicing

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