17-44903606-C-A

Position:

• chr17-44903606-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001258400.2(FAM187A):​c.-224C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,404,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: FAM187A NM_001258400.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.201

Genes affected

FAM187A (HGNC:35153): (family with sequence similarity 187 member A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

GFAP (HGNC:4235): (glial fibrillary acidic protein) This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

CCDC103 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM187A	NM_001258400.2	c.-224C>A		5_prime_UTR_variant	1/1	ENST00000331733.5
GFAP	NM_002055.5	c.*3741G>T		3_prime_UTR_variant	9/9	ENST00000588735.3
CCDC103	NM_213607.3	c.*789C>A		3_prime_UTR_variant	4/4	ENST00000417826.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM187A	ENST00000331733.5	c.-224C>A		5_prime_UTR_variant	1/1	1	NM_001258400.2	P1
CCDC103	ENST00000417826.3	c.*789C>A		3_prime_UTR_variant	4/4	1	NM_213607.3	P1
GFAP	ENST00000588735.3	c.*3741G>T		3_prime_UTR_variant	9/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.0000966 AC: 121 AN: 1252624 Hom.: 0 Cov.: 32 AF XY: 0.0000976 AC XY: 59 AN XY: 604760

Gnomad4 AFR exome AF: 0.000581

Gnomad4 AMR exome AF: 0.000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000907

Gnomad4 SAS exome AF: 0.0000544

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000874

Gnomad4 OTH exome AF: 0.0000578

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74382

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.000336

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.34
DANN	Benign	0.55

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

LitVar

Other links and lift over

dbSNP: rs144369192; hg19: chr17-42980974;