chr7-102749659-G-A

Variant names:

• chr7-102749659-G-A
• rs1793234765
• NM_001145268.2:c.451+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001145268.2(FAM185A):​c.451+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000454 in 1,320,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: FAM185A NM_001145268.2 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.82
• Publications: 0 publications found

Genes affected

FAM185A (HGNC:22412): (family with sequence similarity 185 member A)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.55979645 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.1, offset of -22, new splice context is: gagGTgaac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145268.2. 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
	FAM185A	NM_001145268.2	MANE Select	c.451+1G>A		splice_donor intron	N/A	NP_001138740.2	Q8N0U4-1
	FAM185A	NM_001350987.2		c.451+1G>A		splice_donor intron	N/A	NP_001337916.2
	FAM185A	NM_001145269.2		c.210+242G>A		intron	N/A	NP_001138741.2	Q8N0U4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM185A	ENST00000413034.3	TSL:5 MANE Select	c.451+1G>A		splice_donor intron	N/A	ENSP00000395340.2	Q8N0U4-1
	FAM185A	ENST00000950232.1		c.451+1G>A		splice_donor intron	N/A	ENSP00000620291.1
	FAM185A	ENST00000880455.1		c.429+23G>A		intron	N/A	ENSP00000550514.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000454 AC: 6 AN: 1320928 Hom.: 0 Cov.: 33 AF XY: 0.00000155 AC XY: 1 AN XY: 645238

African (AFR) AF: 0.00 AC: 0 AN: 28762

American (AMR) AF: 0.00 AC: 0 AN: 21292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19304

East Asian (EAS) AF: 0.00 AC: 0 AN: 35416

South Asian (SAS) AF: 0.00 AC: 0 AN: 64490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3930

European-Non Finnish (NFE) AF: 0.00000573 AC: 6 AN: 1048016

Other (OTH) AF: 0.00 AC: 0 AN: 54616

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		6.8
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.37		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1793234765; hg19: chr7-102390106;