NM_001378454.1:c.7724G>A

Variant names:

• chr2-73489683-G-A
• rs3820700
• NM_001378454.1:c.7724G>A

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.7724G>A​(p.Ser2575Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,613,854 control chromosomes in the GnomAD database, including 16,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2575G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1271 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14863 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.36
• Publications: 34 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=0.0017927587).
• BP6: Variant 2-73489683-G-A is Benign according to our data. Variant chr2-73489683-G-A is described in ClinVar as Benign. ClinVar VariationId is 383774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.21 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.7724G>A	p.Ser2575Asn	missense	Exon 10 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.7724G>A	p.Ser2575Asn	missense	Exon 10 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.7724G>A	p.Ser2575Asn	missense	Exon 10 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.7598G>A	p.Ser2533Asn	missense	Exon 9 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000423048.5	TSL:1	n.2555G>A		non_coding_transcript_exon	Exon 3 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18957 AN: 151956 Hom.: 1272 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0808

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.134 AC: 33514 AN: 249504 AF XY: 0.139

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0523

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.139 AC: 203585 AN: 1461778 Hom.: 14863 Cov.: 33 AF XY: 0.141 AC XY: 102416 AN XY: 727190

African (AFR) AF: 0.107 AC: 3568 AN: 33480

American (AMR) AF: 0.0546 AC: 2444 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3464 AN: 26136

East Asian (EAS) AF: 0.240 AC: 9541 AN: 39700

South Asian (SAS) AF: 0.169 AC: 14545 AN: 86258

European-Finnish (FIN) AF: 0.154 AC: 8241 AN: 53358

Middle Eastern (MID) AF: 0.146 AC: 842 AN: 5768

European-Non Finnish (NFE) AF: 0.137 AC: 152890 AN: 1111960

Other (OTH) AF: 0.133 AC: 8050 AN: 60394

GnomAD4 genome AF: 0.125 AC: 18961 AN: 152076 Hom.: 1271 Cov.: 32 AF XY: 0.125 AC XY: 9296 AN XY: 74330

African (AFR) AF: 0.101 AC: 4200 AN: 41494

American (AMR) AF: 0.0807 AC: 1233 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 475 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1139 AN: 5162

South Asian (SAS) AF: 0.175 AC: 842 AN: 4812

European-Finnish (FIN) AF: 0.149 AC: 1571 AN: 10564

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.135 AC: 9165 AN: 67976

Other (OTH) AF: 0.122 AC: 257 AN: 2110

Alfa AF: 0.133 Hom.: 6542

Bravo AF: 0.118

TwinsUK AF: 0.144 AC: 535

ALSPAC AF: 0.141 AC: 542

ESP6500AA AF: 0.0982 AC: 376

ESP6500EA AF: 0.130 AC: 1073

ExAC AF: 0.138 AC: 16617

Asia WGS AF: 0.182 AC: 631 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.133

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Alstrom syndrome (3)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.4
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.0050	D
Vest4		0.21
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.097
gMVP		0.082
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3820700; hg19: chr2-73716810; COSMIC: COSV52506859;