2-99162272-A-G

Position:

• chr2-99162272-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_145199.3(LIPT1):​c.315A>G​(p.Thr105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,612,940 control chromosomes in the GnomAD database, including 2,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (575 hom., cov: 31)
  • Exomes 𝑓: 0.028 (1835 hom.)
• Consequence: LIPT1 NM_145199.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.37

Genes affected

LIPT1 (HGNC:29569): (lipoyltransferase 1) The process of transferring lipoic acid to proteins is a two-step process. The first step is the activation of lipoic acid by lipoate-activating enzyme to form lipoyl-AMP. For the second step, the protein encoded by this gene transfers the lipoyl moiety to apoproteins. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 13. Read-through transcription also exists between this gene and the neighboring downstream mitochondrial ribosomal protein L30 (MRPL30) gene. [provided by RefSeq, Mar 2011]

MITD1 (HGNC:25207): (microtubule interacting and trafficking domain containing 1) Abscission, the separation of daughter cells at the end of cytokinesis, is effected by endosomal sorting complexes required for transport III (ESCRT-III). The protein encoded by this gene functions as a homodimer, with the N-termini binding to a subset of ESCRT-III subunits and the C-termini binding to membranes. The encoded protein regulates ESCRT-III activity and is required for proper cytokinesis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-99162272-A-G is Benign according to our data. Variant chr2-99162272-A-G is described in ClinVar as [Benign]. Clinvar id is 380548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-99162272-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPT1	NM_145199.3	c.315A>G	p.Thr105=	synonymous_variant	2/2	ENST00000651691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPT1	ENST00000651691.1	c.315A>G	p.Thr105=	synonymous_variant	2/2		NM_145199.3	P1

Frequencies

GnomAD3 genomes AF: 0.0620 AC: 9428 AN: 152150 Hom.: 577 Cov.: 31

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0895

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.0323

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0626

GnomAD3 exomes AF: 0.0532 AC: 13262 AN: 249484 Hom.: 788 AF XY: 0.0468 AC XY: 6312 AN XY: 135004

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.0255

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0420

GnomAD4 exome AF: 0.0280 AC: 40859 AN: 1460670 Hom.: 1835 Cov.: 32 AF XY: 0.0271 AC XY: 19727 AN XY: 726706

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.0255

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0379

GnomAD4 genome AF: 0.0620 AC: 9434 AN: 152270 Hom.: 575 Cov.: 31 AF XY: 0.0621 AC XY: 4623 AN XY: 74466

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.0895

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.0319

Gnomad4 FIN AF: 0.0217

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0624

Alfa AF: 0.0298 Hom.: 221

Bravo AF: 0.0717

Asia WGS AF: 0.0960 AC: 334 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 22, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.24
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3791211; hg19: chr2-99778735; COSMIC: COSV60740171; COSMIC: COSV60740171;