NM_173607.5:c.627A>C

Variant names:

• chr14-35081144-A-C
• NM_173607.5:c.627A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_173607.5(FAM177A1):​c.627A>C​(p.Ser209Ser) variant causes a synonymous 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FAM177A1 NM_173607.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0450
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-35081144-A-C is Benign according to our data. Variant chr14-35081144-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3771124.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.045 with no splicing effect.

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.627A>C	p.Ser209Ser	synonymous	Exon 5 of 5	NP_775878.2	Q8N128-2
	FAM177A1	NM_001079519.1		c.558A>C	p.Ser186Ser	synonymous	Exon 7 of 7	NP_001072987.1	Q8N128-1
	FAM177A1	NM_001289022.3		c.558A>C	p.Ser186Ser	synonymous	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.627A>C	p.Ser209Ser	synonymous	Exon 5 of 5	ENSP00000280987.4	Q8N128-2
	FAM177A1	ENST00000382406.7	TSL:1	c.558A>C	p.Ser186Ser	synonymous	Exon 6 of 6	ENSP00000371843.3	Q8N128-1
	FAM177A1	ENST00000555211.6	TSL:4	c.558A>C	p.Ser186Ser	synonymous	Exon 7 of 7	ENSP00000451508.2	Q8N128-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1460722 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111194

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.5
DANN	Benign	0.85
PhyloP100		0.045
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

hg19: chr14-35550350;