Genetic Variant MAML3:p.Gln508_Gln509dup (chr4-139889909-T-TTGCTGC) – 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.1521_1526dupGCAGCA(p.Gln508_Gln509dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0039 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0012 ( 36 hom. )

Failed GnomAD Quality Control

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 -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_018717.5

BS2

High AC in GnomAd4 at 186 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.1521_1526dupGCAGCA	p.Gln508_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.1521_1526dupGCAGCA	p.Gln508_Gln509dup	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000421180.1	Q96JK9
MAML3	ENST00000899537.1		c.1521_1526dupGCAGCA	p.Gln508_Gln509dup	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000569596.1
MAML3	ENST00000502696.1	TSL:2	c.109-159248_109-159243dupGCAGCA		intron	N/A	ENSP00000422783.1	H0Y920

Frequencies

GnomAD3 genomes

AF:

0.00385

AC:

184

AN:

47818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00151

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00206

Gnomad ASJ

AF:

0.0328

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000780

Gnomad FIN

AF:

0.00120

Gnomad MID

AF:

0.0104

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.00776

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00125

AC:

1782

AN:

1428132

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

833

AN XY:

707644

show subpopulations

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

African (AFR)

AF:

0.00101

AC:

AN:

32736

American (AMR)

AF:

0.000544

AC:

AN:

44092

Ashkenazi Jewish (ASJ)

AF:

0.00483

AC:

123

AN:

25468

East Asian (EAS)

AF:

0.0000515

AC:

AN:

38816

South Asian (SAS)

AF:

0.000281

AC:

AN:

85306

European-Finnish (FIN)

AF:

0.000382

AC:

AN:

52406

Middle Eastern (MID)

AF:

0.000894

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.00137

AC:

1485

AN:

1084776

Other (OTH)

AF:

0.00112

AC:

AN:

58942

⚠️ 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: 0.347

Heterozygous variant carriers

154

230

307

384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00388

AC:

186

AN:

47906

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

AN XY:

23534

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

28500

American (AMR)

AF:

0.00205

AC:

AN:

5356

Ashkenazi Jewish (ASJ)

AF:

0.0328

AC:

AN:

670

East Asian (EAS)

AF:

0.00

AC:

AN:

2310

South Asian (SAS)

AF:

0.000779

AC:

AN:

1284

European-Finnish (FIN)

AF:

0.00120

AC:

AN:

1668

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0135

AC:

AN:

7332

Other (OTH)

AF:

0.00772

AC:

AN:

648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

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:

0.00364

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