11-18475604-A-T

Variant names:

• chr11-18475604-A-T
• NM_144972.5:c.557A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_144972.5(LDHAL6A):​c.557A>T​(p.His186Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDHAL6A NM_144972.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.45

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDHAL6A	NM_144972.5	c.557A>T	p.His186Leu	missense_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.557A>T	p.His186Leu	missense_variant	Exon 4 of 7	2	NM_144972.5	ENSP00000280706.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.58	.;D;D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.018	D
MutationAssessor	Pathogenic	4.3	.;H;H
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-9.8	.;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.55
MutPred		0.72		Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);Loss of disorder (P = 0.0446);
MVP		0.87
MPC		0.14
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.87
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr11-18497151;