rs186449817

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001378454.1(ALMS1):ā€‹c.3942A>Cā€‹(p.Ser1314Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,613,770 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00070 ( 0 hom., cov: 32)
Exomes š‘“: 0.00079 ( 2 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.490
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 2-73450469-A-C is Benign according to our data. Variant chr2-73450469-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 240994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.49 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000698 (106/151946) while in subpopulation NFE AF= 0.00105 (71/67940). AF 95% confidence interval is 0.000849. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALMS1NM_001378454.1 linkuse as main transcriptc.3942A>C p.Ser1314Ser synonymous_variant 8/23 ENST00000613296.6 NP_001365383.1
ALMS1NM_015120.4 linkuse as main transcriptc.3942A>C p.Ser1314Ser synonymous_variant 8/23 NP_055935.4 Q8TCU4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALMS1ENST00000613296.6 linkuse as main transcriptc.3942A>C p.Ser1314Ser synonymous_variant 8/231 NM_001378454.1 ENSP00000482968.1 Q8TCU4-1

Frequencies

GnomAD3 genomes
AF:
0.000698
AC:
106
AN:
151828
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000363
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.00260
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000832
Gnomad FIN
AF:
0.000378
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00104
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000850
AC:
212
AN:
249316
Hom.:
0
AF XY:
0.000954
AC XY:
129
AN XY:
135258
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.000261
Gnomad ASJ exome
AF:
0.00437
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.000980
Gnomad FIN exome
AF:
0.000325
Gnomad NFE exome
AF:
0.00102
Gnomad OTH exome
AF:
0.000826
GnomAD4 exome
AF:
0.000790
AC:
1155
AN:
1461824
Hom.:
2
Cov.:
40
AF XY:
0.000831
AC XY:
604
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00425
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00110
Gnomad4 FIN exome
AF:
0.000543
Gnomad4 NFE exome
AF:
0.000773
Gnomad4 OTH exome
AF:
0.000712
GnomAD4 genome
AF:
0.000698
AC:
106
AN:
151946
Hom.:
0
Cov.:
32
AF XY:
0.000660
AC XY:
49
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.000362
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00260
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000832
Gnomad4 FIN
AF:
0.000378
Gnomad4 NFE
AF:
0.00105
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000946
Hom.:
1
Bravo
AF:
0.000646
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 30, 2018- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 27, 2022- -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024ALMS1: BP4, BP7 -
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 30, 2020- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 17, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Alstrom syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.54
DANN
Benign
0.47
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs186449817; hg19: chr2-73677596; API