rs137854442

Variant names:

• chr8-143728601-G-A
• rs137854442
• NM_198488.5:c.860C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-143728601-G-A
• chr8-143728601-G-C
• chr8-143728601-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_198488.5(FAM83H):​c.860C>T​(p.Ser287Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,608,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: FAM83H NM_198488.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 13 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1405631).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000893 (13/1455934) while in subpopulation AMR AF = 0.000114 (5/44042). AF 95% confidence interval is 0.0000441. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM83H	NM_198488.5	c.860C>T	p.Ser287Leu	missense_variant	Exon 5 of 5	ENST00000388913.4	NP_940890.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM83H	ENST00000388913.4	c.860C>T	p.Ser287Leu	missense_variant	Exon 5 of 5	5	NM_198488.5	ENSP00000373565.3
FAM83H	ENST00000650760.1	c.1463C>T	p.Ser488Leu	missense_variant	Exon 5 of 5			ENSP00000499217.1
FAM83H	ENST00000395103.2	n.38C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2		ENSP00000378535.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000212 AC: 5 AN: 235646 AF XY: 0.0000231

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000885

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000952

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.00000893 AC: 13 AN: 1455934 Hom.: 0 Cov.: 38 AF XY: 0.0000138 AC XY: 10 AN XY: 724164

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.000114 AC: 5 AN: 44042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 85626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110584

Other (OTH) AF: 0.0000166 AC: 1 AN: 60204

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000399 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000166 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.0041
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.042
Sift	Benign	0.13	T
Sift4G	Uncertain	0.026	D
Polyphen		0.82	P
Vest4		0.18
MutPred		0.42		Loss of glycosylation at S287 (P = 0.0225);
MVP		0.043
MPC		0.41
ClinPred		0.44	T
GERP RS		4.8
Varity_R		0.21
gMVP		0.64
Mutation Taster		=96/4	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: rs137854442; hg19: chr8-144810771; COSMIC: COSV66354661; COSMIC: COSV66354661;