Genetic Variant NM_001145113.3:c.905G>T (chr17-81940837-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001145113.3(MYADML2):c.905G>T(p.Arg302Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000147 in 1,356,130 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. R302H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

MYADML2
NM_001145113.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.72

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

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.905G>T	p.Arg302Leu	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.905G>T	p.Arg302Leu	missense	Exon 3 of 3	ENSP00000386702.2	A6NDP7
MYADML2	ENST00000858967.1		c.905G>T	p.Arg302Leu	missense	Exon 2 of 2	ENSP00000529026.1
PYCR1	ENST00000579366.5	TSL:3	c.-111G>T		5_prime_UTR	Exon 1 of 4	ENSP00000462398.1	J3KSA9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1356130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

662026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30952

American (AMR)

AF:

0.00

AC:

AN:

33440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22290

East Asian (EAS)

AF:

0.00

AC:

AN:

35268

South Asian (SAS)

AF:

0.0000138

AC:

AN:

72214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

9.49e-7

AC:

AN:

1053856

Other (OTH)

AF:

0.00

AC:

AN:

56144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0019

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.6

PhyloP100

3.7

PrimateAI

Uncertain

0.51

PROVEAN

Benign

1.1

REVEL

Benign

0.18

Sift

Benign

0.36

Sift4G

Benign

0.38

Polyphen

0.99

Vest4

0.75

MutPred

0.67

Loss of disorder (P = 0.0366)

MVP

0.11

ClinPred

0.92

GERP RS

3.7

PromoterAI

0.0060

Neutral

(source)

Varity_R

0.31

gMVP

0.74

Mutation Taster

=33/67

disease causing

(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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over