NM_144972.5:c.993G>C

Variant names:

• chr11-18478864-G-C
• rs1214646054
• NM_144972.5:c.993G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144972.5(LDHAL6A):​c.993G>C​(p.Lys331Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LDHAL6A NM_144972.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.173
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10666391).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144972.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDHAL6A	NM_144972.5	MANE Select	c.993G>C	p.Lys331Asn	missense	Exon 7 of 7	NP_659409.2
	LDHAL6A	NM_001144071.2		c.993G>C	p.Lys331Asn	missense	Exon 8 of 8	NP_001137543.1	Q6ZMR3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDHAL6A	ENST00000280706.3	TSL:2 MANE Select	c.993G>C	p.Lys331Asn	missense	Exon 7 of 7	ENSP00000280706.2	Q6ZMR3
	LDHAL6A	ENST00000396213.7	TSL:1	c.993G>C	p.Lys331Asn	missense	Exon 8 of 8	ENSP00000379516.3	Q6ZMR3
	TSG101	ENST00000860301.1		c.*21+1661C>G		intron	N/A	ENSP00000530360.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458020 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725394

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33202

American (AMR) AF: 0.00 AC: 0 AN: 43680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 85788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111016

Other (OTH) AF: 0.00 AC: 0 AN: 60236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.17
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.036
Sift	Benign	0.054	T
Sift4G	Benign	0.29	T
Polyphen		0.0050	B
Vest4		0.15
MutPred		0.40		Loss of ubiquitination at K331 (P = 0.0218)
MVP		0.54
MPC		0.11
ClinPred		0.065	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1214646054; hg19: chr11-18500411;