rs16953073

Positions:

• chr15-51507191-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378457.1(DMXL2):​c.2707A>G​(p.Asn903Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,611,372 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N903N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: DMXL2 NM_001378457.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.02

Genes affected

DMXL2 (HGNC:2938): (Dmx like 2) This gene encodes a protein with 12 WD domains. Proteins with WD domains are involved in many functions including participation in signal transduction pathways. Participation of the encoded protein in regulation of the Notch signaling pathway has been demonstrated in vitro using several human cell lines (PMID:20810660). A gene encoding a similar protein is located on chromosome 5. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DMXL2
• BP4: Computational evidence support a benign effect (MetaRNN=0.004383117).
• BP6: Variant 15-51507191-T-C is Benign according to our data. Variant chr15-51507191-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 377078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00528 (804/152334) while in subpopulation AFR AF= 0.0179 (746/41580). AF 95% confidence interval is 0.0169. There are 8 homozygotes in gnomad4. There are 350 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMXL2	NM_001378457.1	c.2707A>G	p.Asn903Asp	missense_variant	16/44	ENST00000560891.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMXL2	ENST00000560891.6	c.2707A>G	p.Asn903Asp	missense_variant	16/44	1	NM_001378457.1	A1
DMXL2	ENST00000543779.6	c.2707A>G	p.Asn903Asp	missense_variant	16/43	1		P4
DMXL2	ENST00000251076.9	c.2707A>G	p.Asn903Asp	missense_variant	16/43	1		A1
DMXL2	ENST00000449909.7	c.2707A>G	p.Asn903Asp	missense_variant	16/41	1

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 805 AN: 152216 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

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: 0.0000147

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00135 AC: 338 AN: 250648 Hom.: 2 AF XY: 0.00102 AC XY: 138 AN XY: 135524

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.000930

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000493 AC: 720 AN: 1459038 Hom.: 4 Cov.: 29 AF XY: 0.000435 AC XY: 316 AN XY: 725968

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.000717

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000929

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152334 Hom.: 8 Cov.: 32 AF XY: 0.00470 AC XY: 350 AN XY: 74494

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.00574

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.00173 AC: 7 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	0.90	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.33	T;T;T
Polyphen		0.049	B;.;.
Vest4		0.26
MVP		0.57
MPC		0.26
ClinPred		0.021	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.24

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: rs16953073; hg19: chr15-51799388;