Genetic Variant FAM177A1:p.Pro6Ala (chr14-35046479-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_173607.5(FAM177A1):c.16C>G(p.Pro6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. P6T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FAM177A1
NM_173607.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.124

Publications

0 publications found

Variant links:

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

FAM177A1 links:

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ACMG classification

Classification was made for transcript

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=0.04677558).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM177A1	NM_173607.5	MANE Select	c.16C>G	p.Pro6Ala	missense	Exon 1 of 5	NP_775878.2	Q8N128-2
FAM177A1	NM_001079519.1		c.-28-26C>G		intron	N/A	NP_001072987.1	Q8N128-1
FAM177A1	NM_001289022.3		c.-28-26C>G		intron	N/A	NP_001275951.1	Q8N128-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM177A1	ENST00000280987.9	TSL:1 MANE Select	c.16C>G	p.Pro6Ala	missense	Exon 1 of 5	ENSP00000280987.4	Q8N128-2
FAM177A1	ENST00000382406.7	TSL:1	c.-28-26C>G		intron	N/A	ENSP00000371843.3	Q8N128-1
FAM177A1	ENST00000927548.1		c.16C>G	p.Pro6Ala	missense	Exon 1 of 3	ENSP00000597607.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000438

AC:

AN:

228320

AF XY:

0.00000802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000606

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1438206

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

713388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32038

American (AMR)

AF:

0.00

AC:

AN:

42454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25652

East Asian (EAS)

AF:

0.0000527

AC:

AN:

37958

South Asian (SAS)

AF:

0.00

AC:

AN:

83274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101230

Other (OTH)

AF:

0.00

AC:

AN:

59114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.011

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.45

M_CAP

Benign

0.048

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

PhyloP100

0.12

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.56

REVEL

Benign

0.027

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.18

MutPred

0.39

Gain of helix (P = 0.0093)

MVP

0.25

MPC

0.015

ClinPred

0.13

GERP RS

0.41

PromoterAI

0.48

Neutral

(source)

gMVP

0.11

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over