4-139889909-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr4-139889909-TTGCTGCTGCTGCTGCTGCTGC-T
• rs58015886
• NM_018717.5:c.1506_1526delGCAGCAGCAGCAGCAGCAGCA

Variant summary

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

The NM_018717.5(MAML3):​c.1506_1526delGCAGCAGCAGCAGCAGCAGCA​(p.Gln503_Gln509del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00124 in 1,476,644 control chromosomes in the GnomAD database, including 13 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (9 hom., cov: 0)
  • Exomes 𝑓: 0.00076 (4 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 = 0.0153 (734/47904) while in subpopulation AFR AF= 0.024 (685/28494). AF 95% confidence interval is 0.0225. There are 9 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 734 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAML3	NM_018717.5	c.1506_1526delGCAGCAGCAGCAGCAGCAGCA	p.Gln503_Gln509del	disruptive_inframe_deletion	Exon 2 of 5	ENST00000509479.6	NP_061187.3
MAML3	XM_047415929.1	c.1506_1526delGCAGCAGCAGCAGCAGCAGCA	p.Gln503_Gln509del	disruptive_inframe_deletion	Exon 2 of 5		XP_047271885.1
MAML3	XM_047415930.1	c.1506_1526delGCAGCAGCAGCAGCAGCAGCA	p.Gln503_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.1506_1526delGCAGCAGCAGCAGCAGCAGCA	p.Gln503_Gln509del	disruptive_inframe_deletion	Exon 2 of 5	1	NM_018717.5	ENSP00000421180.1
MAML3	ENST00000502696.1	c.109-159263_109-159243delGCAGCAGCAGCAGCAGCAGCA		intron_variant	Intron 1 of 3	2		ENSP00000422783.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 734 AN: 47816 Hom.: 9 Cov.: 0

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00389

Gnomad SAS AF: 0.00390

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.0140

GnomAD4 exome AF: 0.000764 AC: 1091 AN: 1428740 Hom.: 4 AF XY: 0.000774 AC XY: 548 AN XY: 707954

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.000658

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00379

Gnomad4 SAS exome AF: 0.00253

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.000831

GnomAD4 genome AF: 0.0153 AC: 734 AN: 47904 Hom.: 9 Cov.: 0 AF XY: 0.0146 AC XY: 344 AN XY: 23534

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.00243

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00390

Gnomad4 SAS AF: 0.00312

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.0139

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;