4-139890138-C-T

Variant names:

• chr4-139890138-C-T
• rs200939015
• NM_018717.5:c.1298G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_018717.5(MAML3):​c.1298G>A​(p.Arg433Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000952 in 1,613,696 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (5 hom.)
• Consequence: MAML3 NM_018717.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34
• Publications: 5 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34445488).
• BS2: High AC in GnomAd4 at 130 AD gene.

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.1298G>A	p.Arg433Gln	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.1298G>A	p.Arg433Gln	missense	Exon 2 of 5	ENSP00000421180.1	Q96JK9
	MAML3	ENST00000899537.1		c.1298G>A	p.Arg433Gln	missense	Exon 2 of 5	ENSP00000569596.1
	MAML3	ENST00000502696.1	TSL:2	c.109-159471G>A		intron	N/A	ENSP00000422783.1	H0Y920

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 130 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000567 AC: 141 AN: 248842 AF XY: 0.000570

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000963 AC: 1407 AN: 1461446 Hom.: 5 Cov.: 35 AF XY: 0.000889 AC XY: 646 AN XY: 726978

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53144

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00120 AC: 1336 AN: 1111864

Other (OTH) AF: 0.000795 AC: 48 AN: 60374

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74456

African (AFR) AF: 0.000193 AC: 8 AN: 41526

American (AMR) AF: 0.00118 AC: 18 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00148 AC: 101 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000968 Hom.: 1

Bravo AF: 0.000869

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000480 AC: 2

ESP6500EA AF: 0.00118 AC: 10

ExAC AF: 0.000512 AC: 62

EpiCase AF: 0.00104

EpiControl AF: 0.00113

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	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.25
Sift	Benign	0.29	T
Sift4G	Benign	0.74	T
Polyphen		1.0	D
Vest4		0.89
MVP		0.46
MPC		0.94
ClinPred		0.049	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.43
Mutation Taster		=50/50

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

dbSNP: rs200939015; hg19: chr4-140811292; COSMIC: COSV99045576; COSMIC: COSV99045576;