rs6546838

Variant names:

• chr2-73452153-A-G
• rs6546838
• NM_001378454.1:c.5626A>G

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.5626A>G​(p.Ile1876Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,613,200 control chromosomes in the GnomAD database, including 65,890 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I1876I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.38 (15469 hom., cov: 32)
  • Exomes 𝑓: 0.24 (50421 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.208
• Publications: 45 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=8.530406E-7).
• BP6: Variant 2-73452153-A-G is Benign according to our data. Variant chr2-73452153-A-G is described in ClinVar as Benign. ClinVar VariationId is 383758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 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.5626A>G	p.Ile1876Val	missense	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.5626A>G	p.Ile1876Val	missense	Exon 8 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.5626A>G	p.Ile1876Val	missense	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.5500A>G	p.Ile1834Val	missense	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000423048.5	TSL:1	n.457A>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58109 AN: 151340 Hom.: 15410 Cov.: 32

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.00708

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.216

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.338

GnomAD2 exomes AF: 0.265 AC: 66041 AN: 249018 AF XY: 0.248

Gnomad AFR exome AF: 0.771

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.00607

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.244 AC: 356086 AN: 1461732 Hom.: 50421 Cov.: 38 AF XY: 0.239 AC XY: 174147 AN XY: 727152

African (AFR) AF: 0.767 AC: 25668 AN: 33476

American (AMR) AF: 0.407 AC: 18181 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4906 AN: 26132

East Asian (EAS) AF: 0.0122 AC: 486 AN: 39692

South Asian (SAS) AF: 0.167 AC: 14444 AN: 86252

European-Finnish (FIN) AF: 0.232 AC: 12370 AN: 53388

Middle Eastern (MID) AF: 0.244 AC: 1406 AN: 5768

European-Non Finnish (NFE) AF: 0.237 AC: 263586 AN: 1111948

Other (OTH) AF: 0.249 AC: 15039 AN: 60390

GnomAD4 genome AF: 0.384 AC: 58230 AN: 151468 Hom.: 15469 Cov.: 32 AF XY: 0.378 AC XY: 27942 AN XY: 73974

African (AFR) AF: 0.756 AC: 31319 AN: 41410

American (AMR) AF: 0.372 AC: 5658 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 660 AN: 3458

East Asian (EAS) AF: 0.00709 AC: 36 AN: 5078

South Asian (SAS) AF: 0.153 AC: 721 AN: 4718

European-Finnish (FIN) AF: 0.244 AC: 2566 AN: 10514

Middle Eastern (MID) AF: 0.224 AC: 65 AN: 290

European-Non Finnish (NFE) AF: 0.240 AC: 16260 AN: 67770

Other (OTH) AF: 0.334 AC: 701 AN: 2098

Alfa AF: 0.280 Hom.: 26605

Bravo AF: 0.411

TwinsUK AF: 0.229 AC: 850

ALSPAC AF: 0.234 AC: 900

ESP6500AA AF: 0.726 AC: 2708

ESP6500EA AF: 0.239 AC: 1951

ExAC AF: 0.267 AC: 32305

Asia WGS AF: 0.123 AC: 428 AN: 3476

EpiCase AF: 0.232

EpiControl AF: 0.237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	0.060
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.097
DANN	Benign	0.67
DEOGEN2	Benign	0.0060	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.061	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.21
PrimateAI	Benign	0.25	T
Sift4G	Benign	1.0	T
Vest4		0.0090
ClinPred		0.0012	T
GERP RS		-3.3
PromoterAI		-0.0031	Neutral
Varity_R		0.0098
gMVP		0.039
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: rs6546838; hg19: chr2-73679280; COSMIC: COSV107272368; COSMIC: COSV107272368;