Genetic Variant DMRTA1:p.Arg3Trp (chr9-22447072-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_022160.3(DMRTA1):c.7C>T(p.Arg3Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,608,318 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 19 hom. )

Consequence

DMRTA1
NM_022160.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.935

Publications

5 publications found

Variant links:

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]

DMRTA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00441435).

BP6

Variant 9-22447072-C-T is Benign according to our data. Variant chr9-22447072-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 769751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 gene

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.7C>T	p.Arg3Trp	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.7C>T	p.Arg3Trp	missense	Exon 1 of 2	ENSP00000319651.1	Q5VZB9

Frequencies

GnomAD3 genomes

AF:

0.00292

AC:

445

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00438

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00283

AC:

665

AN:

234798

AF XY:

0.00277

show subpopulations

Gnomad AFR exome

AF:

0.000974

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.000311

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00356

Gnomad NFE exome

AF:

0.00446

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00420

AC:

6110

AN:

1456000

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

2889

AN XY:

724076

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

32970

American (AMR)

AF:

0.00288

AC:

128

AN:

44382

Ashkenazi Jewish (ASJ)

AF:

0.000424

AC:

AN:

25960

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39242

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85474

European-Finnish (FIN)

AF:

0.00371

AC:

193

AN:

52034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00499

AC:

5535

AN:

1110008

Other (OTH)

AF:

0.00361

AC:

217

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

361

722

1084

1445

1806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00292

AC:

445

AN:

152318

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

213

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41592

American (AMR)

AF:

0.00438

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00438

AC:

298

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00394

Hom.:

Bravo

AF:

0.00306

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000275

AC:

ESP6500EA

AF:

0.00362

AC:

ExAC

AF:

0.00241

AC:

284

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.67

M_CAP

Benign

0.034

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

PhyloP100

0.94

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.64

REVEL

Benign

0.080

Sift

Uncertain

0.011

Sift4G

Uncertain

0.028

Polyphen

0.99

Vest4

0.27

MVP

0.66

MPC

0.30

ClinPred

0.033

GERP RS

3.2

PromoterAI

-0.056

Neutral

(source)

Varity_R

0.089

gMVP

0.22

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over