4-139889909-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGCTGC

Variant names:

• chr4-139889909-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-T
• rs58015886
• NM_018717.5:c.1494_1526delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_018717.5(MAML3):​c.1494_1526delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA​(p.Gln499_Gln509del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00181 in 1,476,640 control chromosomes in the GnomAD database, including 29 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (6 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: MAML3 NM_018717.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_018717.5
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0236 (1130/47908) while in subpopulation AFR AF= 0.0359 (1023/28498). AF 95% confidence interval is 0.0341. There are 6 homozygotes in gnomad4. There are 535 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAML3	NM_018717.5	c.1494_1526delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln499_Gln509del	disruptive_inframe_deletion	Exon 2 of 5	ENST00000509479.6	NP_061187.3
MAML3	XM_047415929.1	c.1494_1526delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln499_Gln509del	disruptive_inframe_deletion	Exon 2 of 5		XP_047271885.1
MAML3	XM_047415930.1	c.1494_1526delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln499_Gln509del	disruptive_inframe_deletion	Exon 2 of 3		XP_047271886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAML3	ENST00000509479.6	c.1494_1526delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln499_Gln509del	disruptive_inframe_deletion	Exon 2 of 5	1	NM_018717.5	ENSP00000421180.1
MAML3	ENST00000502696.1	c.109-159275_109-159243delGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCA		intron_variant	Intron 1 of 3	2		ENSP00000422783.1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 1132 AN: 47820 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00784

Gnomad ASJ AF: 0.00448

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00546

Gnomad FIN AF: 0.000600

Gnomad MID AF: 0.0104

Gnomad NFE AF: 0.00518

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.00336 AC: 574 AN: 171060 Hom.: 9 AF XY: 0.00298 AC XY: 279 AN XY: 93608

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.00285

Gnomad ASJ exome AF: 0.00192

Gnomad EAS exome AF: 0.000173

Gnomad SAS exome AF: 0.00301

Gnomad FIN exome AF: 0.0000670

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.00483

GnomAD4 exome AF: 0.00108 AC: 1542 AN: 1428732 Hom.: 23 AF XY: 0.00109 AC XY: 773 AN XY: 707954

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.00220

Gnomad4 ASJ exome AF: 0.00129

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000364

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.0236 AC: 1130 AN: 47908 Hom.: 6 Cov.: 0 AF XY: 0.0227 AC XY: 535 AN XY: 23534

Gnomad4 AFR AF: 0.0359

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.00448

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00545

Gnomad4 FIN AF: 0.000600

Gnomad4 NFE AF: 0.00518

Gnomad4 OTH AF: 0.0247

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs58015886; hg19: chr4-140811063;