17-81940944-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001145113.3(MYADML2):c.798C>A(p.Asn266Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,550,476 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N266N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 3 hom. )

Consequence

MYADML2
NM_001145113.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.819

Publications

4 publications found

Variant links:

Genes affected

MYADML2 (HGNC:34548): (myeloid associated differentiation marker like 2) Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MYADML2 links:

PYCR1 (HGNC:9721): (pyrroline-5-carboxylate reductase 1) This gene encodes an enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline. This enzyme may also play a physiologic role in the generation of NADP(+) in some cell types. The protein forms a homopolymer and localizes to the mitochondrion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

PYCR1 Gene-Disease associations (from GenCC):

autosomal recessive cutis laxa type 2B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
PYCR1-related de Barsy syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics
geroderma osteodysplastica
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PYCR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049141943).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145113.3. 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
	MYADML2	NM_001145113.3	MANE Select	c.798C>A	p.Asn266Lys	missense	Exon 3 of 3	NP_001138585.2	A6NDP7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYADML2	ENST00000409745.2	TSL:1 MANE Select	c.798C>A	p.Asn266Lys	missense	Exon 3 of 3	ENSP00000386702.2	A6NDP7
PYCR1	ENST00000579366.5	TSL:3	c.-218C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000462398.1	J3KSA9
MYADML2	ENST00000858967.1		c.798C>A	p.Asn266Lys	missense	Exon 2 of 2	ENSP00000529026.1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000302

AC:

AN:

155590

AF XY:

0.000327

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000550

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.000606

AC:

847

AN:

1398260

Hom.:

Cov.:

AF XY:

0.000586

AC XY:

404

AN XY:

689600

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

31596

American (AMR)

AF:

0.000308

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.000429

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.0000414

AC:

AN:

48258

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000708

AC:

764

AN:

1078872

Other (OTH)

AF:

0.000500

AC:

AN:

57984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

112

168

224

280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000342

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41458

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00122

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000238

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.4

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0045

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.17

M_CAP

Benign

0.0041

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

0.82

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.5

REVEL

Benign

0.029

Sift

Benign

0.049

Sift4G

Benign

0.58

Polyphen

0.0030

Vest4

0.050

MutPred

0.50

Gain of methylation at N266 (P = 0.001)

MVP

0.014

ClinPred

0.0066

GERP RS

0.30

PromoterAI

-0.0028

Neutral

(source)

Varity_R

0.071

gMVP

0.31

Mutation Taster

=77/23

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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