Genetic Variant LYSMD2:p.Val75Ile (chr15-51737400-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153374.3(LYSMD2):c.223G>A(p.Val75Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

LYSMD2
NM_153374.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01

Publications

0 publications found

Variant links:

Genes affected

LYSMD2 (HGNC:28571): (LysM domain containing 2)

LYSMD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYSMD2	NM_153374.3 link	c.223G>A	p.Val75Ile	missense_variant	Exon 1 of 3	ENST00000267838.7	NP_699205.1	Q8IV50-1
LYSMD2	NM_001143917.2 link	c.1-12279G>A		intron_variant	Intron 1 of 2		NP_001137389.1	Q8IV50-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LYSMD2	ENST00000267838.7 link	c.223G>A	p.Val75Ile	missense_variant	Exon 1 of 3	1	NM_153374.3	ENSP00000267838.3	Q8IV50-1
LYSMD2	ENST00000454181.6 link	c.1-12279G>A		intron_variant	Intron 1 of 2	1		ENSP00000410424.2	Q8IV50-2
LYSMD2	ENST00000560491.2 link	c.-1+440G>A		intron_variant	Intron 1 of 2	3		ENSP00000453933.1	Q8IV50-2
LYSMD2	ENST00000558126.1 link	c.83-12409G>A		intron_variant	Intron 1 of 2	5		ENSP00000452715.1	H0YK98

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1305566

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

643896

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26398

American (AMR)

AF:

0.00

AC:

AN:

24476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22734

East Asian (EAS)

AF:

0.00

AC:

AN:

27738

South Asian (SAS)

AF:

0.00

AC:

AN:

71284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4194

European-Non Finnish (NFE)

AF:

9.59e-7

AC:

AN:

1042398

Other (OTH)

AF:

0.00

AC:

AN:

53836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151794

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41352

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67904

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.223G>A (p.V75I) alteration is located in exon 1 (coding exon 1) of the LYSMD2 gene. This alteration results from a G to A substitution at nucleotide position 223, causing the valine (V) at amino acid position 75 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.2

PhyloP100

4.0

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.19

REVEL

Benign

0.25

Sift

Benign

0.16

Sift4G

Benign

0.21

Polyphen

0.90

Vest4

0.37

MutPred

0.69

Gain of helix (P = 0.0854);

MVP

0.60

MPC

0.40

ClinPred

0.80

GERP RS

4.2

PromoterAI

0.21

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over