chr15-74819251-G-A

Position:

• chr15-74819251-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021819.3(LMAN1L):​c.697G>A​(p.Ala233Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMAN1L NM_021819.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28

Genes affected

LMAN1L (HGNC:6632): (lectin, mannose binding 1 like) This gene encodes a mannose-binding type 1 transmembrane protein that contains an N-terminal lectin-like carbohydrate recognition domain. The encoded protein is similar in structure to lectins found in leguminous plants. This lectin is thought to transport newly synthesized glycoproteins from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMAN1L	NM_021819.3	c.697G>A	p.Ala233Thr	missense_variant	6/14	ENST00000309664.10	NP_068591.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMAN1L	ENST00000309664.10	c.697G>A	p.Ala233Thr	missense_variant	6/14	1	NM_021819.3	ENSP00000310431	P1
LMAN1L	ENST00000379709.7	c.697G>A	p.Ala233Thr	missense_variant	6/13	1		ENSP00000369031
LMAN1L	ENST00000470711.6	n.750G>A		non_coding_transcript_exon_variant	7/7	1
LMAN1L	ENST00000456603.2	n.540G>A		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.697G>A (p.A233T) alteration is located in exon 6 (coding exon 6) of the LMAN1L gene. This alteration results from a G to A substitution at nucleotide position 697, causing the alanine (A) at amino acid position 233 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.84		Gain of phosphorylation at A233 (P = 0.0647);Gain of phosphorylation at A233 (P = 0.0647);
MVP		0.67
MPC		0.41
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-75111592;