chr3-158123876-C-T

Variant names:

• chr3-158123876-C-T
• rs868818936
• NM_001271838.2:c.205C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001271838.2(RSRC1):​c.205C>T​(p.Arg69*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,607,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RSRC1 NM_001271838.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.12
• Publications: 1 publications found

Genes affected

RSRC1 (HGNC:24152): (arginine and serine rich coiled-coil 1) This gene encodes a member of the serine and arginine rich-related protein family. The encoded protein is involved in both constitutive and alternative mRNA splicing. This gene may be associated with schizophrenia. A pseudogene of this gene is located on chromosome 9. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]

RSRC1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 70

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-158123876-C-T is Pathogenic according to our data. Variant chr3-158123876-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 626266.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271838.2. 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
	RSRC1	NM_001271838.2	MANE Select	c.205C>T	p.Arg69*	stop_gained	Exon 3 of 10	NP_001258767.1	Q96IZ7-1
	RSRC1	NM_016625.4		c.205C>T	p.Arg69*	stop_gained	Exon 3 of 10	NP_057709.2
	RSRC1	NM_001271834.2		c.205C>T	p.Arg69*	stop_gained	Exon 3 of 9	NP_001258763.1	Q96IZ7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSRC1	ENST00000611884.5	TSL:5 MANE Select	c.205C>T	p.Arg69*	stop_gained	Exon 3 of 10	ENSP00000481697.1	Q96IZ7-1
	RSRC1	ENST00000295930.7	TSL:1	c.205C>T	p.Arg69*	stop_gained	Exon 3 of 10	ENSP00000295930.3	Q96IZ7-1
	RSRC1	ENST00000312179.10	TSL:1	c.205C>T	p.Arg69*	stop_gained	Exon 3 of 9	ENSP00000308671.6	Q96IZ7-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1455116 Hom.: 0 Cov.: 29 AF XY: 0.00000967 AC XY: 7 AN XY: 724150

African (AFR) AF: 0.0000907 AC: 3 AN: 33076

American (AMR) AF: 0.00 AC: 0 AN: 43448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 85452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1108926

Other (OTH) AF: 0.00 AC: 0 AN: 60004

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74274

African (AFR) AF: 0.0000725 AC: 3 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder, autosomal recessive 70 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		2.1
Vest4		0.46
GERP RS		4.2
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs868818936; hg19: chr3-157841665;