4-139890220-G-A

Position:

• chr4-139890220-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018717.5(MAML3):​c.1216C>T​(p.Pro406Ser) 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: 2.63

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2164082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAML3	NM_018717.5	c.1216C>T	p.Pro406Ser	missense_variant	2/5	ENST00000509479.6	NP_061187.3
MAML3	XM_047415929.1	c.1216C>T	p.Pro406Ser	missense_variant	2/5		XP_047271885.1
MAML3	XM_047415930.1	c.1216C>T	p.Pro406Ser	missense_variant	2/3		XP_047271886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAML3	ENST00000509479.6	c.1216C>T	p.Pro406Ser	missense_variant	2/5	1	NM_018717.5	ENSP00000421180	P1
MAML3	ENST00000502696.1	c.111-159553C>T		intron_variant		2		ENSP00000422783

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

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

Jun 03, 2024

The c.1216C>T (p.P406S) alteration is located in exon 2 (coding exon 2) of the MAML3 gene. This alteration results from a C to T substitution at nucleotide position 1216, causing the proline (P) at amino acid position 406 to be replaced by a serine (S). 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	0.069
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.022
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Benign	0.17	T
Sift4G	Uncertain	0.046	D
Polyphen		0.84	P
Vest4		0.11
MutPred		0.16		Loss of glycosylation at P406 (P = 0.0167);
MVP		0.33
MPC		0.24
ClinPred		0.47	T
GERP RS		5.7
Varity_R		0.066
gMVP		0.53

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: chr4-140811374;