15-59207289-G-A

Position:

• chr15-59207289-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000288235.9(MYO1E):​c.1530+1392C>T variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO1E ENST00000288235.9 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

Genes affected

LDHAL6B (HGNC:21481): (lactate dehydrogenase A like 6B) Predicted to enable L-lactate dehydrogenase activity. Predicted to be involved in pyruvate metabolic process. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MYO1E (HGNC:7599): (myosin IE) This gene encodes a member of the nonmuscle class I myosins which are a subgroup of the unconventional myosin protein family. The unconventional myosin proteins function as actin-based molecular motors. Class I myosins are characterized by a head (motor) domain, a regulatory domain and a either a short or long tail domain. Among the class I myosins, this protein is distinguished by a long tail domain that is involved in crosslinking actin filaments. This protein localizes to the cytoplasm and may be involved in intracellular movement and membrane trafficking. Mutations in this gene are the cause of focal segmental glomerulosclerosis-6. This gene has been referred to as myosin IC in the literature but is distinct from the myosin IC gene located on chromosome 17. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDHAL6B	NM_033195.3	c.349G>A	p.Gly117Ser	missense_variant	1/1	ENST00000307144.6	NP_149972.1
MYO1E	NM_004998.4	c.1530+1392C>T		intron_variant		ENST00000288235.9	NP_004989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDHAL6B	ENST00000307144.6	c.349G>A	p.Gly117Ser	missense_variant	1/1		NM_033195.3	ENSP00000302393	P1
MYO1E	ENST00000288235.9	c.1530+1392C>T		intron_variant		1	NM_004998.4	ENSP00000288235	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.349G>A (p.G117S) alteration is located in exon 1 (coding exon 1) of the LDHAL6B gene. This alteration results from a G to A substitution at nucleotide position 349, causing the glycine (G) at amino acid position 117 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.064
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.024	D
Sift4G	Benign	0.072	T
Polyphen		0.99	D
Vest4		0.49
MutPred		0.81		Loss of catalytic residue at G117 (P = 0.0411);
MVP		0.95
MPC		0.15
ClinPred		0.99	D
GERP RS		1.5
Varity_R		0.44
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-59499488;