5-119110178-A-C

Variant names:

• chr5-119110178-A-C
• rs772342945
• NM_001290321.3:c.392A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001290321.3(DMXL1):​c.392A>C​(p.Tyr131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,445,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y131C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DMXL1 NM_001290321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.12
• Publications: 0 publications found

Genes affected

DMXL1 (HGNC:2937): (Dmx like 1) The protein encoded by this gene is a member of the WD repeat superfamily of proteins, which have regulatory functions. This gene is expressed in many tissue types including several types of eye tissue, and it has been associated with ocular phenotypes. In addition, it is upregulated in cultured cells that overexpress growth factor independence 1B, a transcription factor that is essential for hematopoietic cell development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10082075).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290321.3. 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
	DMXL1	NM_001290321.3	MANE Select	c.392A>C	p.Tyr131Ser	missense	Exon 5 of 44	NP_001277250.1	F5H269
	DMXL1	NM_001349239.2		c.392A>C	p.Tyr131Ser	missense	Exon 6 of 45	NP_001336168.1	F5H269
	DMXL1	NM_001349240.2		c.392A>C	p.Tyr131Ser	missense	Exon 6 of 44	NP_001336169.1	Q9Y485

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMXL1	ENST00000539542.6	TSL:1 MANE Select	c.392A>C	p.Tyr131Ser	missense	Exon 5 of 44	ENSP00000439479.1	F5H269
	DMXL1	ENST00000311085.8	TSL:1	c.392A>C	p.Tyr131Ser	missense	Exon 5 of 43	ENSP00000309690.8	Q9Y485
	DMXL1	ENST00000503802.5	TSL:1	c.392A>C	p.Tyr131Ser	missense	Exon 6 of 13	ENSP00000427692.1	E7EMZ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1445710 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719026

African (AFR) AF: 0.00 AC: 0 AN: 32328

American (AMR) AF: 0.00 AC: 0 AN: 40568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25666

East Asian (EAS) AF: 0.0000517 AC: 2 AN: 38682

South Asian (SAS) AF: 0.00 AC: 0 AN: 82632

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107194

Other (OTH) AF: 0.00 AC: 0 AN: 59650

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.74
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		3.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.18
Sift	Benign	0.41	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.35
MutPred		0.53		Gain of disorder (P = 0.0017)
MVP		0.16
MPC		0.076
ClinPred		0.41	T
GERP RS		3.8
Varity_R		0.097
gMVP		0.29
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772342945; hg19: chr5-118445873;