dbSNP rs201446579: ALMS1:p.Thr3274Thr (chr2-73534864-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001378454.1(ALMS1):c.9822C>G(p.Thr3274Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,613,564 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3274T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 9 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.70

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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen

ALMS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001378454.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-73534864-C-G is Benign according to our data. Variant chr2-73534864-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 374508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.7 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (366/152258) while in subpopulation NFE AF = 0.0036 (245/68018). AF 95% confidence interval is 0.00323. There are 0 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.9822C>G	p.Thr3274Thr	synonymous	Exon 12 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.9822C>G	p.Thr3274Thr	synonymous	Exon 12 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.9822C>G	p.Thr3274Thr	synonymous	Exon 12 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.9696C>G	p.Thr3232Thr	synonymous	Exon 11 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000423048.5	TSL:1	n.*241C>G		non_coding_transcript_exon	Exon 5 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

366

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00595

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00360

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00227

AC:

566

AN:

249364

AF XY:

0.00216

show subpopulations

Gnomad AFR exome

AF:

0.000646

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.00566

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00626

Gnomad NFE exome

AF:

0.00286

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00297

AC:

4333

AN:

1461306

Hom.:

Cov.:

AF XY:

0.00292

AC XY:

2120

AN XY:

726966

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33456

American (AMR)

AF:

0.000805

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00444

AC:

116

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.000186

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00661

AC:

353

AN:

53414

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00324

AC:

3605

AN:

1111608

Other (OTH)

AF:

0.00315

AC:

190

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

220

440

660

880

1100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.00240

AC:

366

AN:

152258

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41560

American (AMR)

AF:

0.000915

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00595

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00360

AC:

245

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00298

Hom.:

Bravo

AF:

0.00183

EpiCase

AF:

0.00305

EpiControl

AF:

0.00225

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Alstrom syndrome (3)

not specified (2)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.17

(source)

DANN

Benign

0.45

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over