rs200602575

Variant names:

• chr15-99729449-C-G
• rs200602575
• NM_001284417.2:c.565G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001284417.2(LYSMD4):​c.565G>C​(p.Glu189Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,614,188 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (9 hom.)
• Consequence: LYSMD4 NM_001284417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.942
• Publications: 4 publications found

Genes affected

LYSMD4 (HGNC:26571): (LysM domain containing 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037824273).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000558 (815/1461846) while in subpopulation MID AF = 0.0224 (129/5768). AF 95% confidence interval is 0.0192. There are 9 homozygotes in GnomAdExome4. There are 429 alleles in the male GnomAdExome4 subpopulation. Median coverage is 77. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001284417.2. 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
	LYSMD4	NM_001284417.2	MANE Select	c.565G>C	p.Glu189Gln	missense	Exon 3 of 3	NP_001271346.1	Q5XG99-1
	LYSMD4	NM_152449.4		c.568G>C	p.Glu190Gln	missense	Exon 6 of 6	NP_689662.2
	LYSMD4	NM_001284418.2		c.565G>C	p.Glu189Gln	missense	Exon 3 of 3	NP_001271347.1	Q5XG99-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYSMD4	ENST00000684762.1	MANE Select	c.565G>C	p.Glu189Gln	missense	Exon 3 of 3	ENSP00000506747.1	Q5XG99-1
	LYSMD4	ENST00000344791.6	TSL:1	c.568G>C	p.Glu190Gln	missense	Exon 6 of 6	ENSP00000342840.2	Q5XG99-2
	LYSMD4	ENST00000409796.5	TSL:1	c.565G>C	p.Glu189Gln	missense	Exon 3 of 3	ENSP00000386283.1	Q5XG99-1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000628 AC: 158 AN: 251420 AF XY: 0.000743

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000558 AC: 815 AN: 1461846 Hom.: 9 Cov.: 77 AF XY: 0.000590 AC XY: 429 AN XY: 727226

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00121 AC: 54 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86256

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53376

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5768

European-Non Finnish (NFE) AF: 0.000404 AC: 449 AN: 1112010

Other (OTH) AF: 0.00101 AC: 61 AN: 60396

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74502

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000653 Hom.: 1

Bravo AF: 0.000412

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.94
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.043	D
Sift4G	Benign	0.090	T
Polyphen		0.33	B
Vest4		0.055
MVP		0.29
MPC		0.32
ClinPred		0.026	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.44
Mutation Taster		=94/6	polymorphism

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: rs200602575; hg19: chr15-100269654;