rs769611643

Variant names:

• chr14-35081221-C-T
• rs769611643
• NM_173607.5:c.704C>T

Variant summary

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

The NM_173607.5(FAM177A1):​c.704C>T​(p.Pro235Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,608,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: FAM177A1 NM_173607.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78
• Publications: 0 publications found

Genes affected

FAM177A1 (HGNC:19829): (family with sequence similarity 177 member A1) This gene encodes a member of a conserved protein family. Alternative splicing results in multiple transcript variants. This gene is thought to be associated with susceptibility to juvenile idiopathic arthritis. [provided by RefSeq, Apr 2017]

FAM177A1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, G2P

LOC101927178 (HGNC:):

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=0.16152257).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173607.5. 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
	FAM177A1	NM_173607.5	MANE Select	c.704C>T	p.Pro235Leu	missense	Exon 5 of 5	NP_775878.2	Q8N128-2
	FAM177A1	NM_001079519.1		c.635C>T	p.Pro212Leu	missense	Exon 7 of 7	NP_001072987.1	Q8N128-1
	FAM177A1	NM_001289022.3		c.635C>T	p.Pro212Leu	missense	Exon 6 of 6	NP_001275951.1	Q8N128-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM177A1	ENST00000280987.9	TSL:1 MANE Select	c.704C>T	p.Pro235Leu	missense	Exon 5 of 5	ENSP00000280987.4	Q8N128-2
	FAM177A1	ENST00000382406.7	TSL:1	c.635C>T	p.Pro212Leu	missense	Exon 6 of 6	ENSP00000371843.3	Q8N128-1
	FAM177A1	ENST00000555211.6	TSL:4	c.635C>T	p.Pro212Leu	missense	Exon 7 of 7	ENSP00000451508.2	Q8N128-1

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 7 AN: 151414 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 246108 AF XY: 0.0000301

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1456686 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 14 AN XY: 724520

African (AFR) AF: 0.00 AC: 0 AN: 33306

American (AMR) AF: 0.00 AC: 0 AN: 43500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 84624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110512

Other (OTH) AF: 0.0000831 AC: 5 AN: 60186

GnomAD4 genome AF: 0.0000462 AC: 7 AN: 151414 Hom.: 0 Cov.: 31 AF XY: 0.0000541 AC XY: 4 AN XY: 73918

African (AFR) AF: 0.0000485 AC: 2 AN: 41244

American (AMR) AF: 0.0000660 AC: 1 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

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	0.088
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.020
Sift	Benign	0.043	D
Sift4G	Benign	0.13	T
Polyphen		0.23	B
Vest4		0.42
MutPred		0.28		Loss of glycosylation at P213 (P = 0.0371)
MVP		0.61
MPC		0.11
ClinPred		0.56	D
GERP RS		2.1
Varity_R		0.056
gMVP		0.30
Mutation Taster		=90/10	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: rs769611643; hg19: chr14-35550427;