NM_019100.5:c.511T>C

Variant names:

• chr1-44218428-T-C
• NM_019100.5:c.511T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_019100.5(DMAP1):​c.511T>C​(p.Phe171Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DMAP1 NM_019100.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.45
• Publications: 0 publications found

Genes affected

DMAP1 (HGNC:18291): (DNA methyltransferase 1 associated protein 1) This gene encodes a subunit of several, distinct complexes involved in the repression or activation of transcription. The encoded protein can independently repress transcription and is targeted to replication foci throughout S phase by interacting directly with the N-terminus of DNA methyltransferase 1. During late S phase, histone deacetylase 2 is added to this complex, providing a means to deacetylate histones in transcriptionally inactive heterochromatin following replication. The encoded protein is also a component of the nucleosome acetyltransferase of H4 complex and interacts with the transcriptional corepressor tumor susceptibility gene 101 and the pro-apoptotic death-associated protein 6, among others. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

ENSG00000302536 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019100.5. 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
	DMAP1	NM_019100.5	MANE Select	c.511T>C	p.Phe171Leu	missense	Exon 4 of 10	NP_061973.1	Q9NPF5
	DMAP1	NM_001034023.2		c.511T>C	p.Phe171Leu	missense	Exon 5 of 11	NP_001029195.1	Q9NPF5
	DMAP1	NM_001034024.2		c.511T>C	p.Phe171Leu	missense	Exon 5 of 11	NP_001029196.1	Q9NPF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMAP1	ENST00000372289.7	TSL:1 MANE Select	c.511T>C	p.Phe171Leu	missense	Exon 4 of 10	ENSP00000361363.2	Q9NPF5
	DMAP1	ENST00000315913.9	TSL:1	c.511T>C	p.Phe171Leu	missense	Exon 5 of 11	ENSP00000312697.5	Q9NPF5
	DMAP1	ENST00000361745.10	TSL:1	c.511T>C	p.Phe171Leu	missense	Exon 5 of 11	ENSP00000354697.6	Q9NPF5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Generalized hypotonia;C3553450:Profound global developmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.026	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.022	D
Polyphen		0.98	D
Vest4		0.97
MutPred		0.87		Gain of sheet (P = 0.0827)
MVP		0.45
MPC		1.4
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.76
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr1-44684100;