chr3-93980161-C-T

Variant names:

• chr3-93980161-C-T
• rs143828740
• NM_001174150.2:c.-263C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001174150.2(ARL13B):​c.-263C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00757 in 634,016 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (25 hom.)
• Consequence: ARL13B NM_001174150.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.17
• Publications: 2 publications found

Genes affected

ARL13B (HGNC:25419): (ADP ribosylation factor like GTPase 13B) This gene encodes a member of the ADP-ribosylation factor-like family. The encoded protein is a small GTPase that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. This protein is localized in the cilia and plays a role in cilia formation and in maintenance of cilia. Mutations in this gene are the cause of Joubert syndrome 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

PROS1 (HGNC:9456): (protein S) This gene encodes a vitamin K-dependent plasma protein that functions as a cofactor for the anticoagulant protease, activated protein C (APC) to inhibit blood coagulation. It is found in plasma in both a free, functionally active form and also in an inactive form complexed with C4b-binding protein. Mutations in this gene result in autosomal dominant hereditary thrombophilia. An inactive pseudogene of this locus is located at an adjacent region on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein. [provided by RefSeq, Oct 2015]

PROS1 Gene-Disease associations (from GenCC):

• thrombophilia due to protein S deficiency, autosomal dominant

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• thrombophilia due to protein S deficiency, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• protein S deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary thrombophilia due to congenital protein S deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 3-93980161-C-T is Benign according to our data. Variant chr3-93980161-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 346901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00691 (1052/152332) while in subpopulation NFE AF = 0.0112 (765/68026). AF 95% confidence interval is 0.0106. There are 5 homozygotes in GnomAd4. There are 469 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174150.2. 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
	ARL13B	NM_001174150.2	MANE Select	c.-263C>T		5_prime_UTR	Exon 1 of 10	NP_001167621.1	Q3SXY8-1
	ARL13B	NM_182896.3		c.-263C>T		5_prime_UTR	Exon 1 of 11	NP_878899.1	Q3SXY8-1
	ARL13B	NM_001321328.2		c.-430C>T		5_prime_UTR	Exon 1 of 11	NP_001308257.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARL13B	ENST00000394222.8	TSL:1 MANE Select	c.-263C>T		5_prime_UTR	Exon 1 of 10	ENSP00000377769.3	Q3SXY8-1
	ARL13B	ENST00000471138.5	TSL:1	c.-263C>T		5_prime_UTR	Exon 1 of 11	ENSP00000420780.1	Q3SXY8-1
	ARL13B	ENST00000535334.5	TSL:1	c.-501C>T		5_prime_UTR	Exon 1 of 9	ENSP00000445145.1	Q3SXY8-3

Frequencies

GnomAD3 genomes AF: 0.00692 AC: 1054 AN: 152214 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00680 AC: 719 AN: 105692 AF XY: 0.00674

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.00682

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000283

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00683

GnomAD4 exome AF: 0.00778 AC: 3748 AN: 481684 Hom.: 25 Cov.: 4 AF XY: 0.00745 AC XY: 1924 AN XY: 258218

African (AFR) AF: 0.00179 AC: 25 AN: 13968

American (AMR) AF: 0.00661 AC: 192 AN: 29064

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 172 AN: 16200

East Asian (EAS) AF: 0.00 AC: 0 AN: 29682

South Asian (SAS) AF: 0.00247 AC: 137 AN: 55368

European-Finnish (FIN) AF: 0.00174 AC: 50 AN: 28808

Middle Eastern (MID) AF: 0.00430 AC: 9 AN: 2094

European-Non Finnish (NFE) AF: 0.0106 AC: 2951 AN: 279612

Other (OTH) AF: 0.00788 AC: 212 AN: 26888

GnomAD4 genome AF: 0.00691 AC: 1052 AN: 152332 Hom.: 5 Cov.: 32 AF XY: 0.00630 AC XY: 469 AN XY: 74500

African (AFR) AF: 0.00176 AC: 73 AN: 41592

American (AMR) AF: 0.00784 AC: 120 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10628

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0112 AC: 765 AN: 68026

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00437 Hom.: 1

Bravo AF: 0.00736

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		1.2
PromoterAI		0.0022	Neutral
Mutation Taster		=288/12	polymorphism

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: rs143828740; hg19: chr3-93699005;