9-41127543-C-T

Variant names:

• chr9-41127543-C-T
• rs1480665274
• NM_001085476.4:c.841G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001085476.4(FOXD4L6):​c.841G>A​(p.Ala281Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A281S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXD4L6 NM_001085476.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397
• Publications: 0 publications found

Genes affected

FOXD4L6 (HGNC:31986): (forkhead box D4 like 6) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anatomical structure morphogenesis; cell differentiation; and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

FRG1HP (HGNC:51767): (FSHD region gene 1 family member H, pseudogene)

ENSG00000308937 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0834735).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085476.4. 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
	FOXD4L6	NM_001085476.4	MANE Select	c.841G>A	p.Ala281Thr	missense	Exon 1 of 1	NP_001078945.1	Q3SYB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L6	ENST00000622588.2	TSL:6 MANE Select	c.841G>A	p.Ala281Thr	missense	Exon 1 of 1	ENSP00000484875.1	Q3SYB3
	FRG1HP	ENST00000617940.2	TSL:6	n.412-67558C>T		intron	N/A
	ENSG00000308937	ENST00000837379.1		n.683+1905C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000418 AC: 6 AN: 1434748 Hom.: 0 Cov.: 30 AF XY: 0.00000700 AC XY: 5 AN XY: 714486

African (AFR) AF: 0.0000304 AC: 1 AN: 32932

American (AMR) AF: 0.00 AC: 0 AN: 43818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 85746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102242

Other (OTH) AF: 0.0000168 AC: 1 AN: 59574

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.083	T
PhyloP100		-0.40
Sift4G	Benign	0.15	T
Vest4		0.028
gMVP		0.060

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: rs1480665274; hg19: chr9-70918708;