chr11-18475637-G-C

Variant names:

• chr11-18475637-G-C
• rs1849358004
• NM_144972.5:c.590G>C

Variant summary

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

The NM_144972.5(LDHAL6A):​c.590G>C​(p.Ser197Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,459,548 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDHAL6A NM_144972.5 missense, splice_region
• Scores: Splicing: ADA: 0.006091
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

Genes affected

LDHAL6A (HGNC:28335): (lactate dehydrogenase A like 6A) Predicted to enable L-lactate dehydrogenase activity. Predicted to be involved in carbohydrate metabolic process and carboxylic acid metabolic process. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

TSG101 (HGNC:15971): (tumor susceptibility 101) The protein encoded by this gene belongs to a group of apparently inactive homologs of ubiquitin-conjugating enzymes. The gene product contains a coiled-coil domain that interacts with stathmin, a cytosolic phosphoprotein implicated in tumorigenesis. The protein may play a role in cell growth and differentiation and act as a negative growth regulator. In vitro steady-state expression of this tumor susceptibility gene appears to be important for maintenance of genomic stability and cell cycle regulation. Mutations and alternative splicing in this gene occur in high frequency in breast cancer and suggest that defects occur during breast cancer tumorigenesis and/or progression. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDHAL6A	NM_144972.5	c.590G>C	p.Ser197Thr	missense_variant, splice_region_variant	Exon 4 of 7	ENST00000280706.3	NP_659409.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDHAL6A	ENST00000280706.3	c.590G>C	p.Ser197Thr	missense_variant, splice_region_variant	Exon 4 of 7	2	NM_144972.5	ENSP00000280706.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459548 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726048

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.590G>C (p.S197T) alteration is located in exon 4 (coding exon 4) of the LDHAL6A gene. This alteration results from a G to C substitution at nucleotide position 590, causing the serine (S) at amino acid position 197 to be replaced by a threonine (T). 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	.;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T;.;T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Pathogenic	2.9	.;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	.;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.70	.;P;P
Vest4		0.48
MutPred		0.69		Loss of disorder (P = 0.0611);Loss of disorder (P = 0.0611);Loss of disorder (P = 0.0611);
MVP		0.86
MPC		0.36
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.47
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0061
dbscSNV1_RF	Benign	0.19
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: rs1849358004; hg19: chr11-18497184;