rs77517267

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The ENST00000613296.6(ALMS1):ā€‹c.2535C>Gā€‹(p.Asp845Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D845D) has been classified as Benign.

Frequency

Genomes: š‘“ 0.00064 ( 0 hom., cov: 33)
Exomes š‘“: 0.000078 ( 0 hom. )

Consequence

ALMS1
ENST00000613296.6 missense

Scores

15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -4.91
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.005131662).
BP6
Variant 2-73449062-C-G is Benign according to our data. Variant chr2-73449062-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426397.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000644 (98/152288) while in subpopulation AFR AF= 0.00217 (90/41558). AF 95% confidence interval is 0.0018. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALMS1NM_001378454.1 linkuse as main transcriptc.2535C>G p.Asp845Glu missense_variant 8/23 ENST00000613296.6 NP_001365383.1
ALMS1NM_015120.4 linkuse as main transcriptc.2538C>G p.Asp846Glu missense_variant 8/23 NP_055935.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALMS1ENST00000613296.6 linkuse as main transcriptc.2535C>G p.Asp845Glu missense_variant 8/231 NM_001378454.1 ENSP00000482968 P3Q8TCU4-1

Frequencies

GnomAD3 genomes
AF:
0.000611
AC:
93
AN:
152170
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00205
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000169
AC:
42
AN:
248886
Hom.:
0
AF XY:
0.000141
AC XY:
19
AN XY:
134998
show subpopulations
Gnomad AFR exome
AF:
0.00213
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000780
AC:
114
AN:
1461796
Hom.:
0
Cov.:
40
AF XY:
0.0000688
AC XY:
50
AN XY:
727206
show subpopulations
Gnomad4 AFR exome
AF:
0.00257
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.000281
GnomAD4 genome
AF:
0.000644
AC:
98
AN:
152288
Hom.:
0
Cov.:
33
AF XY:
0.000631
AC XY:
47
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.00217
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000947
ExAC
AF:
0.000166
AC:
20

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024ALMS1: BP4 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 23, 2024Reported as a heterozygous variant in a pediatric patient with HCM who also harbored variants in autosomal dominant genes (PMID: 32746448); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32746448, 26582918) -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 24, 2021This 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 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
0.0050
DANN
Benign
0.56
DEOGEN2
Benign
0.018
T;.;.
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.42
T;T;T
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.0051
T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.27
T
Sift4G
Benign
1.0
T;T;T
Vest4
0.032
MVP
0.085
ClinPred
0.013
T
GERP RS
-6.5
Varity_R
0.027
gMVP
0.020

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: rs77517267; hg19: chr2-73676189; API