dbSNP rs920828573: LYSMD2:p.Val75Phe (chr15-51737400-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_153374.3(LYSMD2):c.223G>T(p.Val75Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000766 in 1,305,566 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. V75I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

LYSMD2
NM_153374.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.01

Publications

0 publications found

Variant links:

Genes affected

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

LYSMD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYSMD2	NM_153374.3 link	c.223G>T	p.Val75Phe	missense_variant	Exon 1 of 3	ENST00000267838.7	NP_699205.1	Q8IV50-1
LYSMD2	NM_001143917.2 link	c.1-12279G>T		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>T	p.Val75Phe	missense_variant	Exon 1 of 3	1	NM_153374.3	ENSP00000267838.3	Q8IV50-1
LYSMD2	ENST00000454181.6 link	c.1-12279G>T		intron_variant	Intron 1 of 2	1		ENSP00000410424.2	Q8IV50-2
LYSMD2	ENST00000560491.2 link	c.-1+440G>T		intron_variant	Intron 1 of 2	3		ENSP00000453933.1	Q8IV50-2
LYSMD2	ENST00000558126.1 link	c.83-12409G>T		intron_variant	Intron 1 of 2	5		ENSP00000452715.1	H0YK98

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1305566

Hom.:

Cov.:

AF XY:

0.00000155

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:

0.0000140

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:

0.00

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

4.3

PhyloP100

4.0

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

0.99

Vest4

0.66

MutPred

0.66

Gain of sheet (P = 0.0011);

MVP

0.88

MPC

0.64

ClinPred

0.98

GERP RS

4.2

PromoterAI

-0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.88

gMVP

0.86

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over