17-44903606-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.201
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 Protein UniProt
FAM187ANM_001258400.2 linkuse as main transcriptc.-224C>T 5_prime_UTR_variant 1/1 ENST00000331733.5 NP_001245329.1
GFAPNM_002055.5 linkuse as main transcriptc.*3741G>A 3_prime_UTR_variant 9/9 ENST00000588735.3 NP_002046.1
CCDC103NM_213607.3 linkuse as main transcriptc.*789C>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
FAM187AENST00000331733.5 linkuse as main transcriptc.-224C>T 5_prime_UTR_variant 1/11 NM_001258400.2 ENSP00000329499 P1
CCDC103ENST00000417826.3 linkuse as main transcriptc.*789C>T 3_prime_UTR_variant 4/41 NM_213607.3 ENSP00000391692 P1Q8IW40-1
GFAPENST00000588735.3 linkuse as main transcriptc.*3741G>A 3_prime_UTR_variant 9/91 NM_002055.5 ENSP00000466598 P1P14136-1

Frequencies

GnomAD3 genomes
AF:
0.00904
AC:
1376
AN:
152230
Hom.:
13
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Primary ciliary dyskinesia 17 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144369192; hg19: chr17-42980974; API