chr8-143728488-G-T

Variant names:

• chr8-143728488-G-T
• rs137854435
• NM_198488.5:c.973C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198488.5(FAM83H):​c.973C>A​(p.Arg325Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000713 in 1,402,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FAM83H NM_198488.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.03
• Publications: 0 publications found

Genes affected

FAM83H (HGNC:24797): (family with sequence similarity 83 member H) The protein encoded by this gene plays an important role in the structural development and calcification of tooth enamel. Defects in this gene are a cause of amelogenesis imperfecta type 3 (AI3). [provided by RefSeq, Mar 2010]

FAM83H Gene-Disease associations (from GenCC):

• amelogenesis imperfecta, type 3A

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198488.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83H	NM_198488.5	MANE Select	c.973C>A	p.Arg325Arg	synonymous	Exon 5 of 5	NP_940890.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM83H	ENST00000388913.4	TSL:5 MANE Select	c.973C>A	p.Arg325Arg	synonymous	Exon 5 of 5	ENSP00000373565.3
	FAM83H	ENST00000650760.1		c.1576C>A	p.Arg526Arg	synonymous	Exon 5 of 5	ENSP00000499217.1
	FAM83H	ENST00000935286.1		c.973C>A	p.Arg325Arg	synonymous	Exon 5 of 5	ENSP00000605345.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402552 Hom.: 0 Cov.: 38 AF XY: 0.00000144 AC XY: 1 AN XY: 692360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31918

American (AMR) AF: 0.00 AC: 0 AN: 36178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 36158

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081166

Other (OTH) AF: 0.00 AC: 0 AN: 58126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.93
PhyloP100		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137854435; hg19: chr8-144810658;