chr4-139889738-C-T

Variant names:

• chr4-139889738-C-T
• NM_018717.5:c.1698G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018717.5(MAML3):​c.1698G>A​(p.Met566Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAML3 NM_018717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29665643).

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.1698G>A	p.Met566Ile	missense	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.1698G>A	p.Met566Ile	missense	Exon 2 of 5	ENSP00000421180.1	Q96JK9
	MAML3	ENST00000899537.1		c.1698G>A	p.Met566Ile	missense	Exon 2 of 5	ENSP00000569596.1
	MAML3	ENST00000502696.1	TSL:2	c.109-159071G>A		intron	N/A	ENSP00000422783.1	H0Y920

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 92

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.053
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.16
Sift	Benign	0.061	T
Sift4G	Benign	0.48	T
Vest4		0.17
MVP		0.39
MPC		0.26
ClinPred		0.31	T
GERP RS		5.8
Varity_R		0.35
gMVP		0.60
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr4-140810892;