rs730882244

Variant names:

• chr14-35077175-T-TA
• rs730882244
• NM_173607.5:c.366dupA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_173607.5(FAM177A1):​c.366dupA​(p.Trp123MetfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FAM177A1 NM_173607.5 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.355
• Publications: 2 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-35077175-T-TA is Pathogenic according to our data. Variant chr14-35077175-T-TA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183348.Status of the report is no_assertion_criteria_provided, 0 stars.

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.366dupA	p.Trp123MetfsTer16	frameshift	Exon 3 of 5	NP_775878.2	Q8N128-2
	FAM177A1	NM_001079519.1		c.297dupA	p.Trp100MetfsTer16	frameshift	Exon 5 of 7	NP_001072987.1	Q8N128-1
	FAM177A1	NM_001289022.3		c.297dupA	p.Trp100MetfsTer16	frameshift	Exon 4 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.366dupA	p.Trp123MetfsTer16	frameshift	Exon 3 of 5	ENSP00000280987.4	Q8N128-2
	FAM177A1	ENST00000382406.7	TSL:1	c.297dupA	p.Trp100MetfsTer16	frameshift	Exon 4 of 6	ENSP00000371843.3	Q8N128-1
	FAM177A1	ENST00000555211.6	TSL:4	c.297dupA	p.Trp100MetfsTer16	frameshift	Exon 5 of 7	ENSP00000451508.2	Q8N128-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Dolichocephaly;C2243051:Macrocephaly;C3714756:Intellectual disability;CN228310:Mild obesity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730882244; hg19: chr14-35546381;