chr8-38404715-T-C

Position:

• chr8-38404715-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286819.2(LETM2):​c.1218+209T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 513,832 control chromosomes in the GnomAD database, including 11,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3299 hom., cov: 33)
  • Exomes 𝑓: 0.21 (8188 hom.)
• Consequence: LETM2 NM_001286819.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.69

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 8-38404715-T-C is Benign according to our data. Variant chr8-38404715-T-C is described in ClinVar as [Benign]. Clinvar id is 1261324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LETM2	NM_001286819.2	c.1218+209T>C		intron_variant		ENST00000379957.9	NP_001273748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LETM2	ENST00000379957.9	c.1218+209T>C		intron_variant		5	NM_001286819.2	ENSP00000369291	P4

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30435 AN: 152066 Hom.: 3293 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.206 AC: 74652 AN: 361648 Hom.: 8188 Cov.: 2 AF XY: 0.200 AC XY: 38652 AN XY: 193024

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.247

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.351

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.200 AC: 30466 AN: 152184 Hom.: 3299 Cov.: 33 AF XY: 0.197 AC XY: 14649 AN XY: 74412

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.339

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.203

Alfa AF: 0.194 Hom.: 376

Bravo AF: 0.210

Asia WGS AF: 0.212 AC: 735 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 32747698) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.098
DANN	Benign	0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs7001340; hg19: chr8-38262233;