rs1553404102

Positions:

• chr2-73452129-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001378454.1(ALMS1):​c.5602C>A​(p.Leu1868Ile) 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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.41

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ALMS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053223163).
• BP6: Variant 2-73452129-C-A is Benign according to our data. Variant chr2-73452129-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 506250.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.5602C>A	p.Leu1868Ile	missense_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.5602C>A	p.Leu1868Ile	missense_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.5602C>A	p.Leu1868Ile	missense_variant	8/23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 08, 2018

p.Leu1869Ile in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 11 have an Isoleucine (Ile) at this position despite high nearby amino aci d conservation. In addition, computational prediction tools do not suggest an im pact to the protein. ACMG/AMP Criteria applied: BP4_Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	3.1
DANN	Benign	0.90
DEOGEN2	Benign	0.012	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.57	T;T;T
Vest4		0.13
MVP		0.11
ClinPred		0.12	T
GERP RS		-1.9
Varity_R		0.027
gMVP		0.029

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: rs1553404102; hg19: chr2-73679256;