9-22447487-C-A

Variant names:

• chr9-22447487-C-A
• rs1361906032
• NM_022160.3:c.422C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_022160.3(DMRTA1):​c.422C>A​(p.Ala141Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,407,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A141V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DMRTA1 NM_022160.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77
• Publications: 0 publications found

Genes affected

DMRTA1 (HGNC:13826): (DMRT like family A1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in germ cell development; regulation of transcription by RNA polymerase II; and sex differentiation. Predicted to act upstream of or within male mating behavior and ovarian follicle development. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022160.3. 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
	DMRTA1	NM_022160.3	MANE Select	c.422C>A	p.Ala141Glu	missense	Exon 1 of 2	NP_071443.2	Q5VZB9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMRTA1	ENST00000325870.3	TSL:1 MANE Select	c.422C>A	p.Ala141Glu	missense	Exon 1 of 2	ENSP00000319651.1	Q5VZB9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407512 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 696206

African (AFR) AF: 0.00 AC: 0 AN: 31568

American (AMR) AF: 0.00 AC: 0 AN: 38316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.00 AC: 0 AN: 36276

South Asian (SAS) AF: 0.00 AC: 0 AN: 81286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085926

Other (OTH) AF: 0.00 AC: 0 AN: 58374

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.38		Loss of MoRF binding (P = 0.0444)
MVP		0.60
MPC		0.72
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.78
Mutation Taster		=37/63	disease causing

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: rs1361906032; hg19: chr9-22447486;