21-46191189-G-T

Position:

• chr21-46191189-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_002340.6(LSS):​c.2114C>A​(p.Thr705Lys) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LSS NM_002340.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.75

Genes affected

LSS (HGNC:6708): (lanosterol synthase) The protein encoded by this gene catalyzes the conversion of (S)-2,3 oxidosqualene to lanosterol. The encoded protein is a member of the terpene cyclase/mutase family and catalyzes the first step in the biosynthesis of cholesterol, steroid hormones, and vitamin D. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78
• PP5: Variant 21-46191189-G-T is Pathogenic according to our data. Variant chr21-46191189-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 834065.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LSS	NM_002340.6	c.2114C>A	p.Thr705Lys	missense_variant	22/22	ENST00000397728.8	NP_002331.3
LSS	NM_001001438.3	c.2114C>A	p.Thr705Lys	missense_variant	22/23		NP_001001438.1
LSS	NM_001145436.2	c.2081C>A	p.Thr694Lys	missense_variant	22/22		NP_001138908.1
LSS	NM_001145437.2	c.1874C>A	p.Thr625Lys	missense_variant	21/21		NP_001138909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LSS	ENST00000397728.8	c.2114C>A	p.Thr705Lys	missense_variant	22/22	1	NM_002340.6	ENSP00000380837	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alopecia-intellectual disability syndrome 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.4	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Benign	0.065	T;T;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.77
MutPred		0.63		Gain of methylation at T705 (P = 0.0089);Gain of methylation at T705 (P = 0.0089);.;.;
MVP		0.61
MPC		0.56
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.79

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: rs746562872; hg19: chr21-47611103;