rs539962457

Variant names:

• chr11-74493615-A-C
• rs539962457
• NM_001144869.3:c.89T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-74493615-A-C
• chr11-74493615-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001144869.3(LIPT2):​c.89T>G​(p.Leu30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,304,740 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L30V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• Publications: 0 publications found

Genes affected

LIPT2 (HGNC:37216): (lipoyl(octanoyl) transferase 2) This gene encodes a mitochondrial protein that catalyzes the transfer of octanoic acid to lipoate-dependent enzymes such as octanoyl-ACP. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

LIPT2-AS1 (HGNC:56172): (LIPT2 antisense RNA 1)

POLD3 (HGNC:20932): (DNA polymerase delta 3, accessory subunit) This gene encodes the 66-kDa subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. The encoded protein plays a role in regulating the activity of DNA polymerase delta through interactions with other subunits and the processivity cofactor proliferating cell nuclear antigen (PCNA). Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]

POLD3 Gene-Disease associations (from GenCC):

• hearing loss disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-74493615-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438640.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144869.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPT2	NM_001144869.3	MANE Select	c.89T>G	p.Leu30Arg	missense	Exon 1 of 2	NP_001138341.1
	LIPT2	NM_001329941.2		c.89T>G	p.Leu30Arg	missense	Exon 1 of 2	NP_001316870.1
	LIPT2	NM_001329942.2		c.89T>G	p.Leu30Arg	missense	Exon 1 of 2	NP_001316871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPT2	ENST00000310109.5	TSL:2 MANE Select	c.89T>G	p.Leu30Arg	missense	Exon 1 of 2	ENSP00000309463.4
	LIPT2-AS1	ENST00000526036.1	TSL:1	n.250A>C		non_coding_transcript_exon	Exon 1 of 2
	LIPT2	ENST00000528085.1	TSL:3	c.32T>G	p.Leu11Arg	missense	Exon 1 of 2	ENSP00000433005.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.66e-7 AC: 1 AN: 1304740 Hom.: 0 Cov.: 52 AF XY: 0.00000156 AC XY: 1 AN XY: 641812

African (AFR) AF: 0.00 AC: 0 AN: 26426

American (AMR) AF: 0.00 AC: 0 AN: 24526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22580

East Asian (EAS) AF: 0.00 AC: 0 AN: 28214

South Asian (SAS) AF: 0.00 AC: 0 AN: 70214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3978

European-Non Finnish (NFE) AF: 9.59e-7 AC: 1 AN: 1042450

Other (OTH) AF: 0.00 AC: 0 AN: 54072

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.72	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.50
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.50
MutPred		0.59		Gain of disorder (P = 0.0143)
MVP		0.36
ClinPred		0.38	T
GERP RS		3.6
PromoterAI		0.062	Neutral
Varity_R		0.34
gMVP		0.70
Mutation Taster		=60/40	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: rs539962457; hg19: chr11-74204660;