NM_006262.4:c.199G>A

Variant names:

• chr12-49295399-G-A
• rs543217008
• NM_006262.4:c.199G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006262.4(PRPH):​c.199G>A​(p.Ala67Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A67P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRPH NM_006262.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• Publications: 0 publications found

Genes affected

PRPH (HGNC:9461): (peripherin) This gene encodes a cytoskeletal protein found in neurons of the peripheral nervous system. The encoded protein is a type III intermediate filament protein with homology to other cytoskeletal proteins such as desmin, and is a different protein that the peripherin found in photoreceptors. Mutations in this gene have been associated with susceptibility to amyotrophic lateral sclerosis. [provided by RefSeq, Jul 2008]

TROAP-AS1 (HGNC:55453): (TROAP and PRPH antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15274042).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006262.4. 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
	PRPH	NM_006262.4	MANE Select	c.199G>A	p.Ala67Thr	missense	Exon 1 of 9	NP_006253.2
	TROAP-AS1	NR_120449.1		n.2673C>T		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPH	ENST00000257860.9	TSL:1 MANE Select	c.199G>A	p.Ala67Thr	missense	Exon 1 of 9	ENSP00000257860.4	P41219-1
	PRPH	ENST00000451891.4	TSL:5	c.-45G>A		5_prime_UTR	Exon 1 of 6	ENSP00000408897.4	F8W835
	TROAP-AS1	ENST00000553259.1	TSL:2	n.2673C>T		non_coding_transcript_exon	Exon 6 of 8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000449 AC: 1 AN: 222720 AF XY: 0.00000814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000590

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000832 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.45	T
Polyphen		0.013	B
Vest4		0.098
MutPred		0.54		Gain of catalytic residue at L71 (P = 0)
MVP		0.68
MPC		0.57
ClinPred		0.15	T
GERP RS		3.7
PromoterAI		-0.023	Neutral
Varity_R		0.055
gMVP		0.49
Mutation Taster		=89/11	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: rs543217008; hg19: chr12-49689182;