chr21-42477323-T-C

Variant names:

• chr21-42477323-T-C
• rs748503692
• NM_080860.4:c.695A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080860.4(RSPH1):​c.695A>G​(p.Asp232Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.940

Genes affected

RSPH1 (HGNC:12371): (radial spoke head component 1) This gene encodes a male meiotic metaphase chromosome-associated acidic protein. This gene is expressed in tissues with motile cilia or flagella, including the trachea, lungs, airway brushings, and testes. Mutations in this gene result in primary ciliary dyskinesia-24. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085549384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.695A>G	p.Asp232Gly	missense_variant	Exon 7 of 9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.581A>G	p.Asp194Gly	missense_variant	Exon 6 of 8		NP_001273435.1
RSPH1	XM_011529786.2	c.623A>G	p.Asp208Gly	missense_variant	Exon 6 of 8		XP_011528088.1
RSPH1	XM_005261208.3	c.488A>G	p.Asp163Gly	missense_variant	Exon 5 of 7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.695A>G	p.Asp232Gly	missense_variant	Exon 7 of 9	1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.581A>G	p.Asp194Gly	missense_variant	Exon 6 of 8	5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.2313A>G		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251270 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457602 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.083	T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.062
Sift	Benign	0.23	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0010	B;.
Vest4		0.18
MutPred		0.17		Loss of solvent accessibility (P = 0.0595);.;
MVP		0.17
MPC		0.13
ClinPred		0.068	T
GERP RS		1.8
Varity_R		0.077
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs748503692; hg19: chr21-43897433;