chr9-100473671-C-T

Variant names:

• chr9-100473671-C-T
• rs760451724
• NM_003692.5:c.127C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003692.5(TMEFF1):​c.127C>T​(p.Pro43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000037 in 1,542,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: TMEFF1 NM_003692.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.966
• Publications: 0 publications found

Genes affected

TMEFF1 (HGNC:11866): (transmembrane protein with EGF like and two follistatin like domains 1) Predicted to enable signaling receptor binding activity. Predicted to be involved in animal organ morphogenesis; neuron projection development; and tissue development. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

MSANTD3-TMEFF1 (HGNC:38838): (MSANTD3-TMEFF1 readthrough) This locus represents naturally occurring read-through transcription from the neighboring MSANTD3 (Myb/SANT-like DNA-binding domain containing 3) and TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1) genes. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18053901).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003692.5. 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
	TMEFF1	NM_003692.5	MANE Select	c.127C>T	p.Pro43Ser	missense	Exon 1 of 10	NP_003683.2
	MSANTD3-TMEFF1	NM_001198812.1		c.419-25094C>T		intron	N/A	NP_001185741.1	Q8IYR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEFF1	ENST00000374879.5	TSL:1 MANE Select	c.127C>T	p.Pro43Ser	missense	Exon 1 of 10	ENSP00000364013.4	Q8IYR6-1
	MSANTD3-TMEFF1	ENST00000502978.1	TSL:2	c.80-25094C>T		intron	N/A	ENSP00000424768.2
	TMEFF1	ENST00000906124.1		c.127C>T	p.Pro43Ser	missense	Exon 1 of 11	ENSP00000576183.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151678 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000288 AC: 4 AN: 138656 AF XY: 0.0000535

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000658

Gnomad NFE exome AF: 0.0000594

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000381 AC: 53 AN: 1390824 Hom.: 0 Cov.: 31 AF XY: 0.0000394 AC XY: 27 AN XY: 686090

African (AFR) AF: 0.00 AC: 0 AN: 30824

American (AMR) AF: 0.0000286 AC: 1 AN: 34984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24962

East Asian (EAS) AF: 0.00 AC: 0 AN: 35300

South Asian (SAS) AF: 0.00 AC: 0 AN: 77718

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.0000465 AC: 50 AN: 1075974

Other (OTH) AF: 0.0000173 AC: 1 AN: 57752

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151678 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74100

African (AFR) AF: 0.0000242 AC: 1 AN: 41286

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67892

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000481 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.97
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.063
Sift	Benign	0.44	T
Sift4G	Benign	0.75	T
Polyphen		0.33	B
Vest4		0.15
MVP		0.36
MPC		0.30
ClinPred		0.088	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.064
gMVP		0.36
Mutation Taster		=89/11	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: rs760451724; hg19: chr9-103235953;