chr4-139889909-T-TTGC

Variant names:

• chr4-139889909-T-TTGC
• rs58015886
• NM_018717.5:c.1524_1526dupGCA

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_018717.5(MAML3):​c.1524_1526dupGCA​(p.Gln509dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (25 hom., cov: 0)
  • Exomes 𝑓: 0.019 (274 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAML3 NM_018717.5 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.616
• Publications: 3 publications found

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]

ENSG00000294637 (HGNC:):

ACMG classification

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

• BP3: Nonframeshift variant in repetitive region in NM_018717.5
• BP6: Variant 4-139889909-T-TTGC is Benign according to our data. Variant chr4-139889909-T-TTGC is described in ClinVar as Benign. ClinVar VariationId is 770352.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

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.1524_1526dupGCA	p.Gln509dup	disruptive_inframe_insertion	Exon 2 of 5	NP_061187.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAML3	ENST00000509479.6	TSL:1 MANE Select	c.1524_1526dupGCA	p.Gln509dup	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000421180.1	Q96JK9
	MAML3	ENST00000899537.1		c.1524_1526dupGCA	p.Gln509dup	disruptive_inframe_insertion	Exon 2 of 5	ENSP00000569596.1
	MAML3	ENST00000502696.1	TSL:2	c.109-159245_109-159243dupGCA		intron	N/A	ENSP00000422783.1	H0Y920

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 2360 AN: 47766 Hom.: 26 Cov.: 0

Gnomad AFR AF: 0.00947

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.0369

Gnomad ASJ AF: 0.0940

Gnomad EAS AF: 0.00303

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.0521

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.0543

GnomAD2 exomes AF: 0.0122 AC: 2083 AN: 171060 AF XY: 0.0122

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.00155

Gnomad FIN exome AF: 0.00556

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0191

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0191 AC: 27280 AN: 1425548 Hom.: 274 Cov.: 0 AF XY: 0.0190 AC XY: 13405 AN XY: 706376

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

African (AFR) AF: 0.00452 AC: 148 AN: 32714

American (AMR) AF: 0.00933 AC: 411 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 444 AN: 25452

East Asian (EAS) AF: 0.00108 AC: 42 AN: 38818

South Asian (SAS) AF: 0.00740 AC: 631 AN: 85268

European-Finnish (FIN) AF: 0.00722 AC: 378 AN: 52350

Middle Eastern (MID) AF: 0.0170 AC: 95 AN: 5582

European-Non Finnish (NFE) AF: 0.0223 AC: 24112 AN: 1082438

Other (OTH) AF: 0.0173 AC: 1019 AN: 58862

⚠️ 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.

GnomAD4 genome AF: 0.0493 AC: 2357 AN: 47854 Hom.: 25 Cov.: 0 AF XY: 0.0449 AC XY: 1055 AN XY: 23504

African (AFR) AF: 0.00944 AC: 269 AN: 28492

American (AMR) AF: 0.0368 AC: 197 AN: 5350

Ashkenazi Jewish (ASJ) AF: 0.0940 AC: 63 AN: 670

East Asian (EAS) AF: 0.00303 AC: 7 AN: 2310

South Asian (SAS) AF: 0.0374 AC: 48 AN: 1284

European-Finnish (FIN) AF: 0.0420 AC: 70 AN: 1668

Middle Eastern (MID) AF: 0.0465 AC: 4 AN: 86

European-Non Finnish (NFE) AF: 0.227 AC: 1653 AN: 7294

Other (OTH) AF: 0.0540 AC: 35 AN: 648

Alfa AF: 0.0206 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=78/22	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs58015886; hg19: chr4-140811063;