rs200956240

Variant names:

• chr4-1815768-C-A
• rs200956240
• NM_012318.3:c.1966G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-1815768-C-A
• chr4-1815768-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_012318.3(LETM1):​c.1966G>T​(p.Ala656Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. A656T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: LETM1 NM_012318.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.74
• Publications: 0 publications found

Genes affected

LETM1 (HGNC:6556): (leucine zipper and EF-hand containing transmembrane protein 1) This gene encodes a protein that is localized to the inner mitochondrial membrane. The protein functions to maintain the mitochondrial tubular shapes and is required for normal mitochondrial morphology and cellular viability. Mutations in this gene cause Wolf-Hirschhorn syndrome, a complex malformation syndrome caused by the deletion of parts of the distal short arm of chromosome 4. Related pseudogenes have been identified on chromosomes 8, 15 and 19. [provided by RefSeq, Oct 2009]

LETM1 Gene-Disease associations (from GenCC):

• neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11000559).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000958 (14/1461836) while in subpopulation AMR AF = 0.000201 (9/44722). AF 95% confidence interval is 0.000104. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012318.3. 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
	LETM1	NM_012318.3	MANE Select	c.1966G>T	p.Ala656Ser	missense	Exon 13 of 14	NP_036450.1	O95202-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LETM1	ENST00000302787.3	TSL:1 MANE Select	c.1966G>T	p.Ala656Ser	missense	Exon 13 of 14	ENSP00000305653.2	O95202-1
	LETM1	ENST00000872452.1		c.2383G>T	p.Ala795Ser	missense	Exon 13 of 14	ENSP00000542511.1
	LETM1	ENST00000872451.1		c.1984G>T	p.Ala662Ser	missense	Exon 13 of 14	ENSP00000542510.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251366 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111996

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152346 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41596

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0085	T
Eigen	Benign	0.074
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.037
Sift	Benign	0.086	T
Sift4G	Benign	0.25	T
Polyphen		0.70	P
Vest4		0.56
MVP		0.37
MPC		0.60
ClinPred		0.36	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.52
Mutation Taster		=85/15	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: rs200956240; hg19: chr4-1817495;