2-3580103-CT-CTT

Variant names:

• chr2-3580103-C-CT
• rs140914434
• NM_001011.4:c.357-3dupT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS2

The NM_001011.4(RPS7):​c.357-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,734 control chromosomes in the GnomAD database, including 8 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: RPS7 NM_001011.4 splice_acceptor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.920
• Publications: 0 publications found

Genes affected

RPS7 (HGNC:10440): (ribosomal protein S7) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S7E family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

RPS7 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia 8

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.25811967 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 0 (no position change), new splice context is: ttttaaactattctttttAGccg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 2-3580103-C-CT is Benign according to our data. Variant chr2-3580103-C-CT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469408.
• BS2: High AC in GnomAd4 at 601 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011.4. 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
	RPS7	NM_001011.4	MANE Select	c.357-3dupT		splice_acceptor intron	N/A	NP_001002.1	P62081

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS7	ENST00000645674.2	MANE Select	c.357-3dupT		splice_acceptor intron	N/A	ENSP00000496757.1	P62081
	RPS7	ENST00000462576.5	TSL:1	c.357-3dupT		splice_acceptor intron	N/A	ENSP00000495273.1	P62081
	RPS7	ENST00000472966.1	TSL:1	n.289dupT		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 600 AN: 152010 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000995 AC: 250 AN: 251164 AF XY: 0.000729

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000356 AC: 520 AN: 1461606 Hom.: 4 Cov.: 32 AF XY: 0.000307 AC XY: 223 AN XY: 727114

African (AFR) AF: 0.0127 AC: 425 AN: 33472

American (AMR) AF: 0.000760 AC: 34 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111788

Other (OTH) AF: 0.000762 AC: 46 AN: 60372

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152128 Hom.: 4 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74380

African (AFR) AF: 0.0134 AC: 558 AN: 41494

American (AMR) AF: 0.00203 AC: 31 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.00410

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Diamond-Blackfan anemia (1)
-	-	1	Diamond-Blackfan anemia 8 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.92
Mutation Taster		=100/0	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: rs140914434; hg19: chr2-3627693;