2-73448717-C-T

Variant names:

• chr2-73448717-C-T
• rs7598901
• NM_001378454.1:c.2190C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378454.1(ALMS1):​c.2190C>T​(p.Phe730Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 1,613,450 control chromosomes in the GnomAD database, including 307,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22487 hom., cov: 31)
  • Exomes 𝑓: 0.62 (284857 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.01
• Publications: 27 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

ENSG00000295621 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-73448717-C-T is Benign according to our data. Variant chr2-73448717-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 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.2190C>T	p.Phe730Phe	synonymous	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.2190C>T	p.Phe730Phe	synonymous	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.2190C>T	p.Phe730Phe	synonymous	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.2064C>T	p.Phe688Phe	synonymous	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.1809C>T	p.Phe603Phe	synonymous	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77090 AN: 151616 Hom.: 22494 Cov.: 31

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.690

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.766

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.653

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.549

GnomAD2 exomes AF: 0.603 AC: 150038 AN: 248858 AF XY: 0.614

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.545

Gnomad ASJ exome AF: 0.627

Gnomad EAS exome AF: 0.777

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.624

GnomAD4 exome AF: 0.619 AC: 905426 AN: 1461718 Hom.: 284857 Cov.: 82 AF XY: 0.622 AC XY: 451994 AN XY: 727176

African (AFR) AF: 0.177 AC: 5908 AN: 33468

American (AMR) AF: 0.543 AC: 24263 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 16417 AN: 26134

East Asian (EAS) AF: 0.747 AC: 29672 AN: 39698

South Asian (SAS) AF: 0.661 AC: 57040 AN: 86258

European-Finnish (FIN) AF: 0.615 AC: 32848 AN: 53418

Middle Eastern (MID) AF: 0.611 AC: 3526 AN: 5768

European-Non Finnish (NFE) AF: 0.628 AC: 698319 AN: 1111870

Other (OTH) AF: 0.620 AC: 37433 AN: 60392

GnomAD4 genome AF: 0.508 AC: 77085 AN: 151732 Hom.: 22487 Cov.: 31 AF XY: 0.514 AC XY: 38113 AN XY: 74158

African (AFR) AF: 0.197 AC: 8154 AN: 41342

American (AMR) AF: 0.559 AC: 8523 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 2150 AN: 3466

East Asian (EAS) AF: 0.767 AC: 3943 AN: 5144

South Asian (SAS) AF: 0.672 AC: 3224 AN: 4800

European-Finnish (FIN) AF: 0.609 AC: 6419 AN: 10542

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.629 AC: 42697 AN: 67874

Other (OTH) AF: 0.549 AC: 1158 AN: 2108

Alfa AF: 0.563 Hom.: 41602

Bravo AF: 0.488

Asia WGS AF: 0.694 AC: 2414 AN: 3478

EpiCase AF: 0.637

EpiControl AF: 0.632

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Alstrom syndrome (4)
-	-	1	ALMS1-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.31
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs7598901; hg19: chr2-73675844; COSMIC: COSV52505511; COSMIC: COSV52505511;