rs1052161

Variant names:

• chr2-73601411-G-A
• rs1052161
• NM_001378454.1:c.12089G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-73601411-G-A
• chr2-73601411-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):​c.12089G>A​(p.Arg4030Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,613,740 control chromosomes in the GnomAD database, including 320,677 homozygotes. 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (25093 hom., cov: 32)
  • Exomes 𝑓: 0.63 (295584 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.72
• Publications: 49 publications found

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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.496577E-7).
• BP6: Variant 2-73601411-G-A is Benign according to our data. Variant chr2-73601411-G-A is described in ClinVar as Benign. ClinVar VariationId is 383764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

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.12089G>A	p.Arg4030Lys	missense	Exon 19 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.12089G>A	p.Arg4030Lys	missense	Exon 19 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.12089G>A	p.Arg4030Lys	missense	Exon 19 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.11963G>A	p.Arg3988Lys	missense	Exon 18 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.11708G>A	p.Arg3903Lys	missense	Exon 17 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84422 AN: 151928 Hom.: 25095 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.745

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.675

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.587

GnomAD2 exomes AF: 0.641 AC: 159886 AN: 249530 AF XY: 0.643

Gnomad AFR exome AF: 0.311

Gnomad AMR exome AF: 0.727

Gnomad ASJ exome AF: 0.683

Gnomad EAS exome AF: 0.756

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.632

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.633 AC: 924990 AN: 1461694 Hom.: 295584 Cov.: 68 AF XY: 0.634 AC XY: 460907 AN XY: 727130

African (AFR) AF: 0.305 AC: 10210 AN: 33474

American (AMR) AF: 0.715 AC: 31974 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 17839 AN: 26136

East Asian (EAS) AF: 0.734 AC: 29129 AN: 39696

South Asian (SAS) AF: 0.664 AC: 57250 AN: 86252

European-Finnish (FIN) AF: 0.632 AC: 33750 AN: 53408

Middle Eastern (MID) AF: 0.623 AC: 3594 AN: 5768

European-Non Finnish (NFE) AF: 0.632 AC: 702730 AN: 1111868

Other (OTH) AF: 0.638 AC: 38514 AN: 60384

GnomAD4 genome AF: 0.555 AC: 84438 AN: 152046 Hom.: 25093 Cov.: 32 AF XY: 0.562 AC XY: 41740 AN XY: 74304

African (AFR) AF: 0.321 AC: 13322 AN: 41478

American (AMR) AF: 0.657 AC: 10054 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2316 AN: 3472

East Asian (EAS) AF: 0.745 AC: 3839 AN: 5150

South Asian (SAS) AF: 0.672 AC: 3238 AN: 4818

European-Finnish (FIN) AF: 0.629 AC: 6641 AN: 10560

Middle Eastern (MID) AF: 0.671 AC: 196 AN: 292

European-Non Finnish (NFE) AF: 0.632 AC: 42976 AN: 67960

Other (OTH) AF: 0.586 AC: 1238 AN: 2112

Alfa AF: 0.615 Hom.: 150947

Bravo AF: 0.546

TwinsUK AF: 0.634 AC: 2350

ALSPAC AF: 0.634 AC: 2442

ESP6500AA AF: 0.340 AC: 1498

ESP6500EA AF: 0.637 AC: 5479

ExAC AF: 0.631 AC: 76544

Asia WGS AF: 0.698 AC: 2428 AN: 3478

EpiCase AF: 0.643

EpiControl AF: 0.635

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Alstrom syndrome (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.010
DANN	Benign	0.28
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	7.5e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		-1.7
PrimateAI	Benign	0.37	T
Sift4G	Benign	0.98	T
Vest4		0.0090
ClinPred		0.0051	T
GERP RS		-6.3
Varity_R		0.032
gMVP		0.077
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1052161; hg19: chr2-73828538; COSMIC: COSV52510863; COSMIC: COSV52510863;