17-44903606-C-T

Position:

• chr17-44903606-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001258400.2(FAM187A):​c.-224C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,404,960 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (13 hom., cov: 32)
  • Exomes 𝑓: 0.016 (195 hom.)
• Consequence: FAM187A NM_001258400.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• 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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0156 (19586/1252612) while in subpopulation NFE AF= 0.018 (18364/1018420). AF 95% confidence interval is 0.0178. There are 195 homozygotes in gnomad4_exome. There are 9205 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00904 AC: 1376 AN: 152230 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.0156 AC: 19586 AN: 1252612 Hom.: 195 Cov.: 32 AF XY: 0.0152 AC XY: 9205 AN XY: 604754

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.00639

Gnomad4 ASJ exome AF: 0.000219

Gnomad4 EAS exome AF: 0.000121

Gnomad4 SAS exome AF: 0.00297

Gnomad4 FIN exome AF: 0.00298

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.00903 AC: 1376 AN: 152348 Hom.: 13 Cov.: 32 AF XY: 0.00835 AC XY: 622 AN XY: 74510

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.00666

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.00926

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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	-0.84
CADD	Benign	0.95
DANN	Benign	0.51

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;