15-59207061-A-T

Variant names:

• chr15-59207061-A-T
• rs780998323
• NM_033195.3:c.121A>T

Variant summary

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

The NM_033195.3(LDHAL6B):​c.121A>T​(p.Thr41Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: LDHAL6B NM_033195.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.43

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05411315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDHAL6B	NM_033195.3	c.121A>T	p.Thr41Ser	missense_variant	Exon 1 of 1	ENST00000307144.6	NP_149972.1
MYO1E	NM_004998.4	c.1531-1576T>A		intron_variant	Intron 14 of 27	ENST00000288235.9	NP_004989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDHAL6B	ENST00000307144.6	c.121A>T	p.Thr41Ser	missense_variant	Exon 1 of 1	6	NM_033195.3	ENSP00000302393.4
MYO1E	ENST00000288235.9	c.1531-1576T>A		intron_variant	Intron 14 of 27	1	NM_004998.4	ENSP00000288235.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121A>T (p.T41S) alteration is located in exon 1 (coding exon 1) of the LDHAL6B gene. This alteration results from a A to T substitution at nucleotide position 121, causing the threonine (T) at amino acid position 41 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	0.070
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.063
DANN	Benign	0.23
DEOGEN2	Benign	0.031	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.075
Sift	Benign	0.12	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.031
MutPred		0.34		Loss of helix (P = 0.028);
MVP		0.37
MPC		0.018
ClinPred		0.14	T
GERP RS		-1.9
Varity_R		0.033
gMVP		0.059

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: rs780998323; hg19: chr15-59499260;