15-59206966-G-A

Position:

• chr15-59206966-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033195.3(LDHAL6B):​c.26G>A​(p.Arg9Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000048 (0 hom.)
• Consequence: LDHAL6B NM_033195.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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]

MYO1E (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21778134).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDHAL6B	NM_033195.3	c.26G>A	p.Arg9Gln	missense_variant	1/1	ENST00000307144.6	NP_149972.1
MYO1E	NM_004998.4	c.1531-1481C>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.26G>A	p.Arg9Gln	missense_variant	1/1	6	NM_033195.3	ENSP00000302393.4
MYO1E	ENST00000288235.9	c.1531-1481C>T		intron_variant		1	NM_004998.4	ENSP00000288235.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461570 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727050

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

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

Mar 15, 2023

The c.26G>A (p.R9Q) 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 26, causing the arginine (R) at amino acid position 9 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	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.12
Sift	Benign	0.043	D
Sift4G	Benign	0.37	T
Polyphen		0.99	D
Vest4		0.18
MutPred		0.42		Loss of MoRF binding (P = 0.0037);
MVP		0.66
MPC		0.065
ClinPred		0.45	T
GERP RS		0.28
Varity_R		0.047
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1217093264; hg19: chr15-59499165;