chr8-38407420-C-T

Variant names:

• chr8-38407420-C-T
• rs757157302
• NM_001286819.2:c.1370C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001286819.2(LETM2):​c.1370C>T​(p.Pro457Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LETM2 NM_001286819.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

Genes affected

LETM2 (HGNC:14648): (leucine zipper and EF-hand containing transmembrane protein 2) Predicted to enable ribosome binding activity. Predicted to be involved in cellular metal ion homeostasis. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

LOC102723716 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12186235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LETM2	NM_001286819.2	c.1370C>T	p.Pro457Leu	missense_variant	Exon 10 of 11	ENST00000379957.9	NP_001273748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LETM2	ENST00000379957.9	c.1370C>T	p.Pro457Leu	missense_variant	Exon 10 of 11	5	NM_001286819.2	ENSP00000369291.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.015	.;T;T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	.;.;L;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.067
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.44	.;B;B;.;.
Vest4		0.23
MutPred		0.19		.;.;Gain of catalytic residue at P457 (P = 0.0523);.;.;
MVP		0.15
MPC		0.059
ClinPred		0.55	D
GERP RS		5.5
Varity_R		0.061
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs757157302; hg19: chr8-38264938;