4-140153050-T-G

Variant summary

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

The NM_018717.5(MAML3):c.278A>C(p.Asn93Thr) 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. 13/21 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAML3 NM_018717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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=0.26387408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAML3	NM_018717.5	c.278A>C	p.Asn93Thr	missense_variant	1/5	ENST00000509479.6
MAML3	XM_047415929.1	c.278A>C	p.Asn93Thr	missense_variant	1/5
MAML3	XM_047415930.1	c.278A>C	p.Asn93Thr	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAML3	ENST00000509479.6	c.278A>C	p.Asn93Thr	missense_variant	1/5	1	NM_018717.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1427698 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 707226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000842 AC: 1

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

Sep 06, 2022

The c.278A>C (p.N93T) alteration is located in exon 1 (coding exon 1) of the MAML3 gene. This alteration results from a A to C substitution at nucleotide position 278, causing the asparagine (N) at amino acid position 93 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	0.96	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.084
Sift	Benign	0.21	T
Sift4G	Benign	0.61	T
Polyphen		0.44	B
Vest4		0.30
MutPred		0.68		Loss of helix (P = 0.0558);
MVP		0.27
MPC		0.37
ClinPred		0.27	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.10

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

LitVar

Other links and lift over

dbSNP: rs747464661; hg19: chr4-141074204;