17-44903606-C-T

Variant names:

• chr17-44903606-C-T
• rs144369192
• NM_001258400.2:c.-224C>T

Variant summary

Our verdict is Benign. The variant received -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, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.201
• Publications: 0 publications found

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]

DNAAF19 (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]

DNAAF19 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 17

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 9205 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258400.2. 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
	FAM187A	NM_001258400.2	MANE Select	c.-224C>T		5_prime_UTR	Exon 1 of 1	NP_001245329.1	A6NFU0
	GFAP	NM_002055.5	MANE Select	c.*3741G>A		3_prime_UTR	Exon 9 of 9	NP_002046.1	P14136-1
	DNAAF19	NM_213607.3	MANE Select	c.*789C>T		3_prime_UTR	Exon 4 of 4	NP_998772.1	Q8IW40-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM187A	ENST00000331733.5	TSL:1 MANE Select	c.-224C>T		5_prime_UTR	Exon 1 of 1	ENSP00000329499.4	A6NFU0
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.*3741G>A		3_prime_UTR	Exon 9 of 9	ENSP00000466598.2	P14136-1
	DNAAF19	ENST00000417826.3	TSL:1 MANE Select	c.*789C>T		3_prime_UTR	Exon 4 of 4	ENSP00000391692.2	Q8IW40-1

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

African (AFR) AF: 0.00287 AC: 79 AN: 27556

American (AMR) AF: 0.00639 AC: 99 AN: 15482

Ashkenazi Jewish (ASJ) AF: 0.000219 AC: 4 AN: 18288

East Asian (EAS) AF: 0.000121 AC: 4 AN: 33070

South Asian (SAS) AF: 0.00297 AC: 164 AN: 55172

European-Finnish (FIN) AF: 0.00298 AC: 87 AN: 29208

Middle Eastern (MID) AF: 0.00257 AC: 9 AN: 3498

European-Non Finnish (NFE) AF: 0.0180 AC: 18364 AN: 1018420

Other (OTH) AF: 0.0149 AC: 776 AN: 51918

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

African (AFR) AF: 0.00399 AC: 166 AN: 41578

American (AMR) AF: 0.00666 AC: 102 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1060 AN: 68028

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.00926

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Primary ciliary dyskinesia (1)
-	1	-	Primary ciliary dyskinesia 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.95
DANN	Benign	0.51
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism

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

dbSNP: rs144369192; hg19: chr17-42980974;