17-44903502-C-T

Position:

• chr17-44903502-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001258400.2(FAM187A):​c.-328C>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 0.000841 in 1,277,138 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: FAM187A NM_001258400.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.29

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM187A	NM_001258400.2	c.-328C>T		5_prime_UTR_variant	1/1	ENST00000331733.5	NP_001245329.1
GFAP	NM_002055.5	c.*3845G>A		3_prime_UTR_variant	9/9	ENST00000588735.3	NP_002046.1
CCDC103	NM_213607.3	c.*685C>T		3_prime_UTR_variant	4/4	ENST00000417826.3	NP_998772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM187A	ENST00000331733.5	c.-328C>T		5_prime_UTR_variant	1/1	1	NM_001258400.2	ENSP00000329499	P1
CCDC103	ENST00000417826.3	c.*685C>T		3_prime_UTR_variant	4/4	1	NM_213607.3	ENSP00000391692	P1
GFAP	ENST00000588735.3	c.*3845G>A		3_prime_UTR_variant	9/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 643 AN: 152194 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000381 AC: 429 AN: 1124826 Hom.: 3 Cov.: 31 AF XY: 0.000352 AC XY: 188 AN XY: 533596

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.000424

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000351

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000632

GnomAD4 genome AF: 0.00423 AC: 645 AN: 152312 Hom.: 4 Cov.: 32 AF XY: 0.00416 AC XY: 310 AN XY: 74494

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00312 Hom.: 1

Bravo AF: 0.00465

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.90
CADD	Benign	0.82
DANN	Benign	0.70

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: rs539555310; hg19: chr17-42980870;