15-99729449-C-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037824273).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 429 alleles in male gnomad4_exome subpopulation. Median coverage is 77. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYSMD4	NM_001284417.2	c.565G>C	p.Glu189Gln	missense_variant	Exon 3 of 3	ENST00000684762.1	NP_001271346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYSMD4	ENST00000684762.1	c.565G>C	p.Glu189Gln	missense_variant	Exon 3 of 3		NM_001284417.2	ENSP00000506747.1

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

GnomAD3 exomes AF: 0.000628 AC: 158 AN: 251420 Hom.: 1 AF XY: 0.000743 AC XY: 101 AN XY: 135880

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 SAS exome AF: 0.000784

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

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000404

Gnomad4 OTH exome AF: 0.00101

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

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00189

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568G>C (p.E190Q) alteration is located in exon 6 (coding exon 4) of the LYSMD4 gene. This alteration results from a G to C substitution at nucleotide position 568, causing the glutamic acid (E) at amino acid position 190 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.033	.;T;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.038	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	.;.;M;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	.;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.043	.;.;D;D
Sift4G	Benign	0.090	T;T;T;T
Polyphen		0.33, 0.79	.;.;B;P
Vest4		0.055
MVP		0.29
MPC		0.32
ClinPred		0.026	T
GERP RS		4.2
Varity_R		0.12
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs200602575; hg19: chr15-100269654;