rs187695569

Variant names:

• chr2-61839871-A-C
• rs187695569
• NM_001201543.2:c.1133T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001201543.2(FAM161A):​c.1133T>G​(p.Leu378Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,614,172 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L378L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (22 hom.)
• Consequence: FAM161A NM_001201543.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 2.17
• Publications: 11 publications found

Genes affected

FAM161A (HGNC:25808): (FAM161 centrosomal protein A) This gene belongs to the FAM161 family. It is expressed mainly in the retina. Mouse studies suggested that this gene is involved in development of retinal progenitors during embryogenesis, and that its activity is restricted to mature photoreceptors after birth. Mutations in this gene cause autosomal recessive retinitis pigmentosa-28. Alternatively spliced transcript variants have been identified.[provided by RefSeq, Jan 2011]

FAM161A Gene-Disease associations (from GenCC):

• retinitis pigmentosa 28

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008030057).
• BP6: Variant 2-61839871-A-C is Benign according to our data. Variant chr2-61839871-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167058.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00378 (575/152284) while in subpopulation AMR AF = 0.00575 (88/15302). AF 95% confidence interval is 0.00478. There are 7 homozygotes in GnomAd4. There are 273 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001201543.2. 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
	FAM161A	NM_001201543.2	MANE Select	c.1133T>G	p.Leu378Arg	missense	Exon 3 of 7	NP_001188472.1	Q3B820-3
	FAM161A	NM_032180.3		c.1133T>G	p.Leu378Arg	missense	Exon 3 of 6	NP_115556.2	Q3B820-1
	FAM161A	NR_037710.2		n.1096T>G		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM161A	ENST00000404929.6	TSL:1 MANE Select	c.1133T>G	p.Leu378Arg	missense	Exon 3 of 7	ENSP00000385158.1	Q3B820-3
	FAM161A	ENST00000405894.3	TSL:1	c.1133T>G	p.Leu378Arg	missense	Exon 3 of 6	ENSP00000385893.3	Q3B820-1
	FAM161A	ENST00000456262.5	TSL:1	n.*648T>G		non_coding_transcript_exon	Exon 3 of 6	ENSP00000396105.1	F8WCZ8

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152166 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00305 AC: 758 AN: 248790 AF XY: 0.00325

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.00855

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00463

GnomAD4 exome AF: 0.00349 AC: 5101 AN: 1461888 Hom.: 22 Cov.: 37 AF XY: 0.00354 AC XY: 2574 AN XY: 727244

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00300 AC: 134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00987 AC: 258 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86258

European-Finnish (FIN) AF: 0.00283 AC: 151 AN: 53420

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.00377 AC: 4195 AN: 1112006

Other (OTH) AF: 0.00389 AC: 235 AN: 60396

GnomAD4 genome AF: 0.00378 AC: 575 AN: 152284 Hom.: 7 Cov.: 32 AF XY: 0.00367 AC XY: 273 AN XY: 74454

African (AFR) AF: 0.000987 AC: 41 AN: 41550

American (AMR) AF: 0.00575 AC: 88 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10608

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00423 AC: 288 AN: 68026

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00397 Hom.: 6

Bravo AF: 0.00391

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00339 AC: 28

ExAC AF: 0.00283 AC: 342

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	1	2	Retinitis pigmentosa 28 (3)
-	-	1	FAM161A-related disorder (1)
-	-	1	not specified (1)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.2
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.13	T
Polyphen		0.98	D
Vest4		0.34
MVP		0.58
MPC		0.054
ClinPred		0.070	T
GERP RS		-3.1
Varity_R		0.54
gMVP		0.31
Mutation Taster		=96/4	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: rs187695569; hg19: chr2-62067006;