rs77517267

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001378454.1(ALMS1):​c.2535C>G​(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. 13/18 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: 𝑓 0.00064 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -4.91

Publications

1 publications found
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]
ALMS1 Gene-Disease associations (from GenCC):
  • Alstrom syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

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 submission is: [Conflicting_classifications_of_pathogenicity].
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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALMS1NM_001378454.1 linkc.2535C>G p.Asp845Glu missense_variant Exon 8 of 23 ENST00000613296.6 NP_001365383.1
ALMS1NM_015120.4 linkc.2535C>G p.Asp845Glu missense_variant Exon 8 of 23 NP_055935.4 Q8TCU4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALMS1ENST00000613296.6 linkc.2535C>G p.Asp845Glu missense_variant Exon 8 of 23 1 NM_001378454.1 ENSP00000482968.1 Q8TCU4-1

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
GnomAD2 exomes
AF:
0.000169
AC:
42
AN:
248886
AF XY:
0.000141
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 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
African (AFR)
AF:
0.00257
AC:
86
AN:
33474
American (AMR)
AF:
0.000201
AC:
9
AN:
44708
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111958
Other (OTH)
AF:
0.000281
AC:
17
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
8
16
24
32
40
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
African (AFR)
AF:
0.00217
AC:
90
AN:
41558
American (AMR)
AF:
0.000392
AC:
6
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68012
Other (OTH)
AF:
0.000947
AC:
2
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
6
12
17
23
29
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
10
ExAC
AF:
0.000166
AC:
20

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
May 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ALMS1: BP4 -

Jul 31, 2025
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Reported as a heterozygous variant in a pediatric patient with HCM who also harbored variants in autosomal dominant genes (PMID: 32746448); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32746448, 26582918) -

not specified Benign:1
Jun 13, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: ALMS1 c.2532C>G (p.Asp844Glu) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 0.00017 in 248886 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome phenotype (0.0014). To our knowledge, no occurrence of c.2532C>G in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 426397). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype Benign:1
May 24, 2021
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
PhyloP100
-4.9
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
PromoterAI
-0.059
Neutral
Varity_R
0.027
gMVP
0.020
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs77517267; hg19: chr2-73676189; API