chr2-45418377-C-T

Variant names:

• chr2-45418377-C-T
• rs527629619
• NM_018079.5:c.2321G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018079.5(SRBD1):​c.2321G>A​(p.Arg774Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R774G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SRBD1 NM_018079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36
• Publications: 0 publications found

Genes affected

SRBD1 (HGNC:25521): (S1 RNA binding domain 1) Predicted to enable mRNA binding activity. Predicted to be a structural constituent of ribosome. Predicted to be involved in translation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3402906).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018079.5. 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
	SRBD1	NM_018079.5	MANE Select	c.2321G>A	p.Arg774Gln	missense	Exon 18 of 21	NP_060549.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRBD1	ENST00000263736.5	TSL:2 MANE Select	c.2321G>A	p.Arg774Gln	missense	Exon 18 of 21	ENSP00000263736.4	Q8N5C6-1
	SRBD1	ENST00000922966.1		c.2321G>A	p.Arg774Gln	missense	Exon 18 of 21	ENSP00000593025.1
	SRBD1	ENST00000490133.5	TSL:2	n.1218G>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460886 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726788

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111628

Other (OTH) AF: 0.00 AC: 0 AN: 60320

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.057
Sift	Benign	0.073	T
Sift4G	Benign	0.52	T
Polyphen		0.30	B
Vest4		0.057
MutPred		0.82		Gain of sheet (P = 0.0477)
MVP		0.30
MPC		0.014
ClinPred		0.51	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.41
Mutation Taster		=97/3	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: rs527629619; hg19: chr2-45645516; COSMIC: COSV55404836; COSMIC: COSV55404836;