chr4-1815739-T-G

Variant names:

• chr4-1815739-T-G
• rs112919287
• NM_012318.3:c.1995A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_012318.3(LETM1):​c.1995A>C​(p.Glu665Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,614,198 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (5 hom., cov: 34)
  • Exomes 𝑓: 0.00044 (7 hom.)
• Consequence: LETM1 NM_012318.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.204
• Publications: 3 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005457282).
• BP6: Variant 4-1815739-T-G is Benign according to our data. Variant chr4-1815739-T-G is described in ClinVar as Benign. ClinVar VariationId is 712521.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00439 (669/152328) while in subpopulation AFR AF = 0.0154 (641/41594). AF 95% confidence interval is 0.0144. There are 5 homozygotes in GnomAd4. There are 319 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.1995A>C	p.Glu665Asp	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.1995A>C	p.Glu665Asp	missense	Exon 13 of 14	ENSP00000305653.2	O95202-1
	LETM1	ENST00000872452.1		c.2412A>C	p.Glu804Asp	missense	Exon 13 of 14	ENSP00000542511.1
	LETM1	ENST00000872451.1		c.2013A>C	p.Glu671Asp	missense	Exon 13 of 14	ENSP00000542510.1

Frequencies

GnomAD3 genomes AF: 0.00439 AC: 668 AN: 152210 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.00192

GnomAD2 exomes AF: 0.00128 AC: 323 AN: 251406 AF XY: 0.000890

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000441 AC: 644 AN: 1461870 Hom.: 7 Cov.: 31 AF XY: 0.000367 AC XY: 267 AN XY: 727236

African (AFR) AF: 0.0158 AC: 530 AN: 33478

American (AMR) AF: 0.00103 AC: 46 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112006

Other (OTH) AF: 0.000944 AC: 57 AN: 60392

GnomAD4 genome AF: 0.00439 AC: 669 AN: 152328 Hom.: 5 Cov.: 34 AF XY: 0.00428 AC XY: 319 AN XY: 74486

African (AFR) AF: 0.0154 AC: 641 AN: 41594

American (AMR) AF: 0.00157 AC: 24 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00176 Hom.: 2

Bravo AF: 0.00505

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00159 AC: 193

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.81
DEOGEN2	Benign	0.00065	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.20
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.14
Sift	Benign	0.81	T
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.27		Loss of ubiquitination at K661 (P = 0.0962)
MVP		0.46
MPC		0.96
ClinPred		0.040	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.34
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112919287; hg19: chr4-1817466;