8-143726344-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_198488.5(FAM83H):c.3117C>T(p.Asp1039=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,612,058 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 34)
  • Exomes 𝑓: 0.00068 (10 hom.)
• Consequence: FAM83H NM_198488.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.27

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 8-143726344-G-A is Benign according to our data. Variant chr8-143726344-G-A is described in ClinVar as [Benign]. Clinvar id is 725599.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.27 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00666 (1015/152354) while in subpopulation AFR AF= 0.023 (956/41580). AF 95% confidence interval is 0.0218. There are 13 homozygotes in gnomad4. There are 495 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 1015 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM83H	NM_198488.5	c.3117C>T	p.Asp1039=	synonymous_variant	5/5	ENST00000388913.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM83H	ENST00000388913.4	c.3117C>T	p.Asp1039=	synonymous_variant	5/5	5	NM_198488.5	P2
FAM83H	ENST00000650760.1	c.3720C>T	p.Asp1240=	synonymous_variant	5/5			A2
FAM83H	ENST00000395103.2	c.2298C>T	p.Asp766=	synonymous_variant, NMD_transcript_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1015 AN: 152236 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

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: 0.00621

GnomAD3 exomes AF: 0.00159 AC: 380 AN: 238596 Hom.: 9 AF XY: 0.00135 AC XY: 176 AN XY: 130730

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000759

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.000675 AC: 986 AN: 1459704 Hom.: 10 Cov.: 83 AF XY: 0.000580 AC XY: 421 AN XY: 726130

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00666 AC: 1015 AN: 152354 Hom.: 13 Cov.: 34 AF XY: 0.00664 AC XY: 495 AN XY: 74500

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00274

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: 0.00614

Alfa AF: 0.00200 Hom.: 3

Bravo AF: 0.00744

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	8.9
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs112740523; hg19: chr8-144808514;