chr2-73557350-T-A

Variant names:

• chr2-73557350-T-A
• rs34617744
• NM_001378454.1:c.10209T>A

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.10209T>A​(p.Thr3403Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,092 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3403T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (124 hom., cov: 32)
  • Exomes 𝑓: 0.013 (782 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.44
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-73557350-T-A is Benign according to our data. Variant chr2-73557350-T-A is described in ClinVar as Benign. ClinVar VariationId is 389388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0834 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.10209T>A	p.Thr3403Thr	synonymous	Exon 14 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.10209T>A	p.Thr3403Thr	synonymous	Exon 14 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.10209T>A	p.Thr3403Thr	synonymous	Exon 14 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.10083T>A	p.Thr3361Thr	synonymous	Exon 13 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000423048.5	TSL:1	n.*628T>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3333 AN: 152174 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0320 AC: 7963 AN: 249118 AF XY: 0.0249

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00189

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.00616

Gnomad OTH exome AF: 0.0242

GnomAD4 exome AF: 0.0125 AC: 18343 AN: 1461800 Hom.: 782 Cov.: 31 AF XY: 0.0116 AC XY: 8422 AN XY: 727194

African (AFR) AF: 0.0302 AC: 1010 AN: 33480

American (AMR) AF: 0.165 AC: 7400 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26132

East Asian (EAS) AF: 0.00804 AC: 319 AN: 39678

South Asian (SAS) AF: 0.00315 AC: 272 AN: 86256

European-Finnish (FIN) AF: 0.0182 AC: 974 AN: 53408

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.00681 AC: 7573 AN: 1111964

Other (OTH) AF: 0.0116 AC: 698 AN: 60394

GnomAD4 genome AF: 0.0220 AC: 3348 AN: 152292 Hom.: 124 Cov.: 32 AF XY: 0.0234 AC XY: 1742 AN XY: 74486

African (AFR) AF: 0.0308 AC: 1282 AN: 41566

American (AMR) AF: 0.0873 AC: 1335 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5186

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4818

European-Finnish (FIN) AF: 0.0211 AC: 224 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00625 AC: 425 AN: 68012

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.00515 Hom.: 3

Bravo AF: 0.0294

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00545

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.4
DANN	Benign	0.57
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs34617744; hg19: chr2-73784477;