chr15-99729539-T-G

Variant names:

• chr15-99729539-T-G
• rs2059350299
• NM_001284417.2:c.475A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001284417.2(LYSMD4):​c.475A>C​(p.Thr159Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LYSMD4 NM_001284417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05688548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYSMD4	NM_001284417.2	c.475A>C	p.Thr159Pro	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.475A>C	p.Thr159Pro	missense_variant	Exon 3 of 3		NM_001284417.2	ENSP00000506747.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.86e-7 AC: 1 AN: 1457124 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.478A>C (p.T160P) alteration is located in exon 6 (coding exon 4) of the LYSMD4 gene. This alteration results from a A to C substitution at nucleotide position 478, causing the threonine (T) at amino acid position 160 to be replaced by a proline (P). 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	0.065
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.39
DANN	Benign	0.23
DEOGEN2	Benign	0.0074	.;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.30	T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.057	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.66	.;.;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.30	.;.;N;N
REVEL	Benign	0.0080
Sift	Benign	0.18	.;.;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0010, 0.24	.;.;B;B
Vest4		0.081
MutPred		0.42		.;.;Loss of catalytic residue at T159 (P = 0.0063);.;
MVP		0.055
MPC		0.18
ClinPred		0.091	T
GERP RS		-2.9
Varity_R		0.061
gMVP		0.33

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: rs2059350299; hg19: chr15-100269744;