4-139889738-C-T

Position:

• chr4-139889738-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/20 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

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 Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAML3	NM_018717.5	c.1698G>A	p.Met566Ile	missense_variant	2/5	ENST00000509479.6	NP_061187.3
MAML3	XM_047415929.1	c.1698G>A	p.Met566Ile	missense_variant	2/5		XP_047271885.1
MAML3	XM_047415930.1	c.1698G>A	p.Met566Ile	missense_variant	2/3		XP_047271886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAML3	ENST00000509479.6	c.1698G>A	p.Met566Ile	missense_variant	2/5	1	NM_018717.5	ENSP00000421180	P1
MAML3	ENST00000502696.1	c.111-159071G>A		intron_variant		2		ENSP00000422783

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 92

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2021

The c.1686G>A (p.M562I) alteration is located in exon 2 (coding exon 2) of the MAML3 gene. This alteration results from a G to A substitution at nucleotide position 1686, causing the methionine (M) at amino acid position 562 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	0.053
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;D
REVEL	Benign	0.16
Sift	Benign	0.061	T;T
Sift4G	Benign	0.48	T;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-140810892;