17-81940458-T-C

Variant names:

• chr17-81940458-T-C
• rs2293099
• NM_001145113.3:c.*360A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145113.3(MYADML2):​c.*360A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 214,374 control chromosomes in the GnomAD database, including 30,613 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (21047 hom., cov: 33)
  • Exomes 𝑓: 0.54 (9566 hom.)
• Consequence: MYADML2 NM_001145113.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• Publications: 5 publications found

Genes affected

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

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: G2P, PanelApp Australia, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• PYCR1-related de Barsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, PanelApp Australia
• geroderma osteodysplastica

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYADML2	NM_001145113.3	c.*360A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000409745.2	NP_001138585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYADML2	ENST00000409745.2	c.*360A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_001145113.3	ENSP00000386702.2
PYCR1	ENST00000582198.5	c.-24+1838A>G		intron_variant	Intron 1 of 6	5		ENSP00000463226.1
PYCR1	ENST00000579366.5	c.-24+292A>G		intron_variant	Intron 1 of 3	3		ENSP00000462398.1

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77759 AN: 151996 Hom.: 21045 Cov.: 33

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.533

GnomAD4 exome AF: 0.539 AC: 33584 AN: 62260 Hom.: 9566 Cov.: 0 AF XY: 0.537 AC XY: 17186 AN XY: 31990

African (AFR) AF: 0.319 AC: 903 AN: 2832

American (AMR) AF: 0.433 AC: 1899 AN: 4388

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 1232 AN: 2018

East Asian (EAS) AF: 0.342 AC: 1769 AN: 5170

South Asian (SAS) AF: 0.481 AC: 1692 AN: 3520

European-Finnish (FIN) AF: 0.635 AC: 1582 AN: 2490

Middle Eastern (MID) AF: 0.561 AC: 157 AN: 280

European-Non Finnish (NFE) AF: 0.590 AC: 22448 AN: 38046

Other (OTH) AF: 0.541 AC: 1902 AN: 3516

GnomAD4 genome AF: 0.511 AC: 77780 AN: 152114 Hom.: 21047 Cov.: 33 AF XY: 0.510 AC XY: 37914 AN XY: 74370

African (AFR) AF: 0.354 AC: 14679 AN: 41472

American (AMR) AF: 0.467 AC: 7136 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2160 AN: 3470

East Asian (EAS) AF: 0.338 AC: 1752 AN: 5176

South Asian (SAS) AF: 0.482 AC: 2326 AN: 4824

European-Finnish (FIN) AF: 0.649 AC: 6865 AN: 10578

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 41010 AN: 67996

Other (OTH) AF: 0.537 AC: 1136 AN: 2116

Alfa AF: 0.513 Hom.: 3399

Bravo AF: 0.491

Asia WGS AF: 0.419 AC: 1463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.67
DANN	Benign	0.28
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2293099; hg19: chr17-79898334;