NM_001144956.3:c.23T>A

Variant names:

• chr1-151721559-T-A
• rs1673735361
• NM_001144956.3:c.23T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001144956.3(RIIAD1):​c.23T>A​(p.Leu8Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,178,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: RIIAD1 NM_001144956.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.26
• Publications: 0 publications found

Genes affected

RIIAD1 (HGNC:26686): (regulatory subunit of type II PKA R-subunit domain containing 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05301878).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144956.3. 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
	RIIAD1	NM_001144956.3	MANE Select	c.23T>A	p.Leu8Gln	missense	Exon 1 of 5	NP_001138428.1	A6NNX1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIIAD1	ENST00000479191.2	TSL:2 MANE Select	c.23T>A	p.Leu8Gln	missense	Exon 1 of 5	ENSP00000419249.1	A6NNX1
	RIIAD1	ENST00000326413.7	TSL:2	c.115-527T>A		intron	N/A	ENSP00000420280.1	C9JPK7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000170 AC: 2 AN: 1178234 Hom.: 0 Cov.: 30 AF XY: 0.00000176 AC XY: 1 AN XY: 569184

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

African (AFR) AF: 0.0000851 AC: 2 AN: 23504

American (AMR) AF: 0.00 AC: 0 AN: 10978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17160

East Asian (EAS) AF: 0.00 AC: 0 AN: 26966

South Asian (SAS) AF: 0.00 AC: 0 AN: 49522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 970642

Other (OTH) AF: 0.00 AC: 0 AN: 47602

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), 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	0.054
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.4
DANN	Benign	0.58
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.016
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.11	T
Polyphen		0.0030	B
Vest4		0.097
MutPred		0.18		Gain of disorder (P = 0.065)
MVP		0.030
ClinPred		0.079	T
GERP RS		-0.96
PromoterAI		-0.033	Neutral
Varity_R		0.12
gMVP		0.18
Mutation Taster		=98/2	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: rs1673735361; hg19: chr1-151694035;